Heterocyclic compounds and uses thereof

ABSTRACT

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/622,259, filed Apr. 10, 2012, and U.S. Provisional PatentApplication No. 61/713,404, filed Oct. 12, 2012, the contents of both ofwhich are incorporated by reference herein in their entireties.

BACKGROUND

The activity of cells can be regulated by external signals thatstimulate or inhibit intracellular events. The process by whichstimulatory or inhibitory signals are transmitted into and within a cellto elicit an intracellular response is referred to as signaltransduction. Over the past decades, cascades of signal transductionevents have been elucidated and found to play a central role in avariety of biological responses. Defects in various components of signaltransduction pathways have been found to account for a vast number ofdiseases, including numerous forms of cancer, inflammatory disorders,metabolic disorders, vascular and neuronal diseases (Gaestel et al.Current Medicinal Chemistry (2007) 14:2214-2234).

Kinases represent a class of important signaling molecules. Kinases cangenerally be classified into protein kinases and lipid kinases, andcertain kinases exhibit dual specificities. Protein kinases are enzymesthat phosphorylate other proteins and/or themselves (i.e.,autophosphorylation). Protein kinases can be generally classified intothree major groups based upon their substrate utilization: tyrosinekinases which predominantly phosphorylate substrates on tyrosineresidues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src,abl), serine/threonine kinases which predominantly phosphorylatesubstrates on serine and/or threonine residues (e.g., mTorC1, mTorC2,ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylatesubstrates on tyrosine, serine and/or threonine residues.

Lipid kinases are enzymes that catalyze the phosphorylation of lipids.These enzymes, and the resulting phosphorylated lipids and lipid-derivedbiologically active organic molecules play a role in many differentphysiological processes, including cell proliferation, migration,adhesion, and differentiation. Certain lipid kinases are membraneassociated and they catalyze the phosphorylation of lipids contained inor associated with cell membranes. Examples of such enzymes includephosphoinositide(s) kinases (e.g., PI3-kinases, PI4-kinases),diacylglycerol kinases, and sphingosine kinases.

The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of themost highly mutated systems in human cancers. PI3K signaling is also akey factor in many other diseases in humans. PI3K signaling is involvedin many disease states including allergic contact dermatitis, rheumatoidarthritis, osteoarthritis, inflammatory bowel diseases, chronicobstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma,disorders related to diabetic complications, and inflammatorycomplications of the cardiovascular system such as acute coronarysyndrome.

PI3Ks are members of a unique and conserved family of intracellularlipid kinases that phosphorylate the 3′-OH group onphosphatidylinositols or phosphoinositides. The PI3K family comprises 15kinases with distinct substrate specificities, expression patterns, andmodes of regulation. The class I PI3Ks (p110α, p110β, p110δ, and p110γ)are typically activated by tyrosine kinases or G-protein coupledreceptors to generate PIP3, which engages downstream effectors such asthose in the Akt/PDK1 pathway, mTOR, the Tec family kinases, and the Rhofamily GTPases. The class II and III PI3Ks play a key role inintracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.The PI3Ks are protein kinases that control cell growth (mTORC1) ormonitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).

The delta (δ) isoform of class I PI3K has been implicated, inparticular, in a number of diseases and biological processes. PI3K-δ isexpressed primarily in hematopoietic cells including leukocytes such asT-cells, dendritic cells, neutrophils, mast cells, B-cells, andmacrophages. PI3K-δ is integrally involved in mammalian immune systemfunctions such as T-cell function, B-cell activation, mast cellactivation, dendritic cell function, and neutrophil activity. Due to itsintegral role in immune system function, PI3K-δ is also involved in anumber of diseases related to undesirable immune response such asallergic reactions, inflammatory diseases, inflammation mediatedangiogenesis, rheumatoid arthritis, and auto-immune diseases such aslupus, asthma, emphysema and other respiratory diseases. Other class IPI3K involved in immune system function includes PI3K-γ, which plays arole in leukocyte signaling and has been implicated in inflammation,rheumatoid arthritis, and autoimmune diseases such as lupus. Forexample, PI3K-γ and PI3K-δ are highly expressed in leukocytes and havebeen associated with adaptive and innate immunity; thus, these PI3Kisoforms can be important mediators in inflammatory disorders andhematologic malignancies.

The gamma (γ) isoform of class I PI3K consists of a catalytic subunitp110γ, which is associated with a p101 regulatory subunit. PI3K-γ isregulated by G protein-coupled receptors (GPCRs) via association withthe β/γ subunits of heterotrimeric G proteins. PI3K-γ is expressedprimarily in hematopoietic cells and cardiomyocytes and is involved ininflammation and mast cell function. Inhibitors of PI3K-γ are useful fortreating a variety of inflammatory diseases, allergies, andcardiovascular diseases, among others.

Unlike PI3K-δ, the beta (β) isoform of class I PI3K appears to beubiquitously expressed. PI3K-β has been implicated primarily in varioustypes of cancer including PTEN-negative cancer (Edgar et al. CancerResearch (2010) 70(3):1164-1172), and HER2-overexpressing cancer such asbreast cancer and ovarian cancer.

SUMMARY

Described herein are compounds capable of selectively inhibiting certainisoform(s) of class I PI3K without substantially affecting the activityof the remaining isoforms of the same class. For example, non-limitingexamples of inhibitors capable of selectively inhibiting PI3K-δ and/orPI3K-γ, but without substantially affecting the activity of PI3K-β aredisclosed. Such inhibitors can be effective in ameliorating diseaseconditions associated with PI3K-δ/γ activity.

In one aspect, provided herein are compounds of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

Cy is aryl or heteroaryl substituted by 0 or 1 occurrence of R³ and 0,1, 2, or 3 occurrence(s) of R⁵;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4occurrence(s) of R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea, or carbonate;

X is —(CH(R⁹))_(z)—;

Y is —N(R⁹)—C(═O)—, —C(═O)—N(R⁹)—, —C(═O)—N(R⁹)—(CHR⁹)—, —N(R⁹)—S(═O)—,—S(═O)—N(R⁹)—, —S(═O)₂—N(R⁹)—, —N(R⁹)—C(═O)—N(R⁹)—, or —N(R⁹)—S(═O)₂—;

z is an integer of 1, 2, 3, or 4;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl,hydroxyl, or nitro;

each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, orheteroalkyl;

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which issubstituted with one or more R¹⁰, R¹¹, R¹², or R¹³, and

wherein R¹⁰, R¹¹, R¹², and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety;

with the proviso that the compound is not:

In some embodiments, the compound of Formula (I) has the structure ofFormula (II):

For example, the compound of Formula (II) can have a structure ofFormula (IIa) or (IIb):

In other embodiments, the compound of Formula (IIa) or (IIb) has thestructure of Formula (IIIa) or (IIIb):

In some embodiments, the compound of Formula (I) has the structure ofFormula (IVa) or Formula (IVb):

In some embodiments, the compound of Formula (IVa) or Formula (IVb) hasthe structure of Formula (Va) or Formula (Vb):

In other embodiments, the compound of Formula (I) has the structure ofFormula (VIa) or Formula (VIb):

In other embodiments, the compound of Formula (VIa) or (VIb) has thestructure of Formula (VIIa) or (VIIb):

In some embodiments, the compound of Formula (VIa) or (VIb) has thestructure of Formula (VIIIa) or (VIIIb):

In some embodiments, the compound of Formula (VIIIa) or (VIIIb) has thestructure of Formula (IXa) or (IXb):

In another aspect, provided herein are compounds of Formula (X) or (XI):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein:

W_(b) ⁵ is N, CHR⁸, or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0 or 1 occurrence of R³ and 0,1, 2, or 3 occurrence(s) of R⁵;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁵)—, —C(R¹⁵)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, orheteroalkyl;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R⁵ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate,or NR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety;

X is —(CH(R¹⁶))_(z)—;

Y is —N(R¹⁶)—C(═O)—, —C(═O)—N(R¹⁶)—, —C(═O)—N(R¹⁶)—(CHR¹⁶)—,—N(R¹⁶)—S(═O)—, —S(═O)—N(R¹⁶)—, —S(═O)₂—N(R¹⁶)—, —N(R¹⁶)—C(═O)—N(R¹⁶),or —N(R¹⁶)—S(═O)₂—;

z is an integer of 1, 2, 3, or 4;

each R¹⁶ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo, or heteroaryl; and

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which issubstituted with one or more R¹⁰, R¹¹, R¹², or R¹³; and

wherein R¹⁰, R¹¹, R¹², and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In another aspect, provided herein are compounds of Formula (XV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

W_(b) ⁵ is N, CHR⁸, or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0 or 1 occurrence of R³ and 0,1, 2, or 3 occurrence(s) of R¹⁷;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁵)—, —C(R¹⁵)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, orheteroalkyl;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl,hydroxyl, or nitro;

each R¹⁷ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate,or NR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety;

X is —(CH(R⁹))_(z)—;

Y is —N(R⁹)—C(═O)—, —C(═O)—N(R⁹)—, —C(═O)—N(R⁹)—(CHR⁹)—, —N(R⁹)—S(═O)—,or —N(R⁹)—S(═O)₂—;

z is an integer of 1, 2, 3, or 4;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, orheteroalkyl;

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which issubstituted with one or more R¹⁰, R¹¹, R¹², or R¹³; and

wherein R¹⁰, R¹¹, R¹², and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety;

with the proviso that said compound is not

In certain embodiments, a compound as disclosed herein selectivelymodulates phosphatidyl inositol-3 kinase (PI3 kinase) delta isoform. Incertain embodiments, the compound selectively inhibits the delta isoformover the alpha or beta isoform. By way of non-limiting example, theratio of selectivity can be greater than a factor of about 10, greaterthan a factor of about 50, greater than a factor of about 100, greaterthan a factor of about 200, greater than a factor of about 400, greaterthan a factor of about 600, greater than a factor of about 800, greaterthan a factor of about 1000, greater than a factor of about 1500,greater than a factor of about 2000, greater than a factor of about5000, greater than a factor of about 10,000, or greater than a factor ofabout 20,000, where selectivity can be measured by IC₅₀, among othermeans. In certain embodiments, the PI3 kinase delta isoform IC₅₀activity of a compound as disclosed herein can be less than about 1000nM, less than about 100 nM, less than about 10 nM, or less than about 1nM.

In certain embodiments, a compound as disclosed herein selectivelymodulates phosphatidyl inositol-3 kinase (PI3 kinase) gamma isoform. Incertain embodiments, the compound selectively inhibits the gamma isoformover the alpha or beta isoform. By way of non-limiting example, theratio of selectivity can be greater than a factor of about 10, greaterthan a factor of about 50, greater than a factor of about 100, greaterthan a factor of about 200, greater than a factor of about 400, greaterthan a factor of about 600, greater than a factor of about 800, greaterthan a factor of about 1000, greater than a factor of about 1500,greater than a factor of about 2000, greater than a factor of about5000, greater than a factor of about 10,000, or greater than a factor ofabout 20,000, where selectivity can be measured by IC₅₀, among othermeans. In certain embodiments, the PI3 kinase gamma isoform IC₅₀activity of a compound as disclosed herein can be less than about 1000nM, less than about 100 nM, less than about 10 nM, or less than about 1nM.

In certain embodiments, provided herein is a composition (e.g., apharmaceutical composition) comprising a compound as described hereinand a pharmaceutically acceptable excipient. In some embodiments,provided herein is a method of inhibiting a phosphatidyl inositol-3kinase (PI3 kinase), comprising contacting the PI3 kinase with aneffective amount of a compound or pharmaceutical composition asdescribed herein. In certain embodiments, a method is provided forinhibiting a phosphatidyl inositol-3 kinase (PI3 kinase) wherein saidPI3 kinase is present in a cell. The inhibition can take place in asubject suffering from a disorder selected from cancer, bone disorder,inflammatory disease, immune disease, nervous system disease (e.g., aneuropsychiatric disorder), metabolic disease, respiratory disease,thrombosis, and cardiac disease, among others. In certain embodiments, asecond therapeutic agent is administered to the subject.

In certain embodiments, a method is provided of selectively inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) delta isoform over PI3kinase alpha or beta isoform wherein the inhibition takes place in acell. Non-limiting examples of the methods disclosed herein can comprisecontacting PI3 kinase delta isoform with an effective amount of acompound or pharmaceutical composition as disclosed herein. In anembodiment, such contact can occur in a cell.

In certain embodiments, a method is provided of selectively inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) delta isoform over PI3kinase alpha or beta isoform wherein the inhibition takes place in asubject suffering from a disorder selected from cancer, bone disorder,inflammatory disease, immune disease, nervous system disease (e.g., aneuropsychiatric disorder), metabolic disease, respiratory disease,thrombosis, and cardiac disease, said method comprising administering aneffective amount of a compound or pharmaceutical composition to saidsubject. In certain embodiments, provided herein is a method of treatinga subject suffering from a disorder associated with phosphatidylinositol-3 kinase (PI3 kinase), said method comprising selectivelymodulating the phosphatidyl inositol-3 kinase (PI3 kinase) delta isoformover PI3 kinase alpha or beta isoform by administering an amount of acompound or pharmaceutical composition to said subject, wherein saidamount is sufficient for selective modulation of PI3 kinase deltaisoform over PI3 kinase alpha or beta isoform.

In certain embodiments, a method is provided of selectively inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) gamma isoform over PI3kinase alpha or beta isoform wherein the inhibition takes place in acell. Non-limiting examples of the methods disclosed herein can comprisecontacting PI3 kinase gamma isoform with an effective amount of acompound or pharmaceutical composition as disclosed herein. In anembodiment, such contact can occur in a cell.

In certain embodiments, a method is provided of selectively inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) gamma isoform over PI3kinase alpha or beta isoform wherein the inhibition takes place in asubject suffering from a disorder selected from cancer, bone disorder,inflammatory disease, immune disease, nervous system disease (e.g., aneuropsychiatric disorder), metabolic disease, respiratory disease,thrombosis, and cardiac disease, said method comprising administering aneffective amount of a compound or pharmaceutical composition to saidsubject. In certain embodiments, provided herein is a method of treatinga subject suffering from a disorder associated with phosphatidylinositol-3 kinase (PI3 kinase), said method comprising selectivelymodulating the phosphatidyl inositol-3 kinase (PI3 kinase) gamma isoformover PI3 kinase alpha or beta isoform by administering an amount of acompound or pharmaceutical composition to said subject, wherein saidamount is sufficient for selective modulation of PI3 kinase gammaisoform over PI3 kinase alpha or beta isoform.

In certain embodiments, provided herein is a method of inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) in a subject, comprisingadministering to the subject an effective amount of a compound providedherein (e.g., a compound of Formula I). In one embodiment, theinhibition takes place in a subject suffering from a disorder selectedfrom a cancer, an inflammatory disease, an immune disease, or arespiratory disease. In one embodiment, the cancer is selected fromacute myeloid leukemia (AML), chronic myeloid leukemia (CML),myelodysplastic syndrome (MDS), myeloproliferative disorders, mast cellcancer, Hodgkin disease, non-Hodgkin lymphomas, diffuse large B-celllymphoma, human lymphotrophic virus type 1 (HTLV-1) leukemia/lymphoma,AIDS-related lymphoma, adult T-cell lymphoma, acute lymphocytic leukemia(ALL), T-cell acute lymphocytic leukemia, B-cell acute lymphoblasticleukemia, chronic lymphocytic leukemia, or multiple myeloma (MM). In oneembodiment, the cancer is leukemia or lymphoma. In one embodiment, theleukemia is selected from B-cell acute lymphoblastic leukemia (B-ALL),acute myeloid leukemia (AML), acute lymphocytic leukemia, chronicmyeloid leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), multiplemyeloma (MM), myelodysplastic syndrome (MDS), or mast cell cancer. Inone embodiment, the lymphoma is selected from diffuse large B-celllymphoma, B-cell immunoblastic lymphoma, small non-cleaved celllymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma,adult T-cell lymphoma, Hodgkin disease, or non-Hodgkin lymphomas. In oneembodiment, the method further comprises administration of one or moretherapeutic agents selected from chemotherapeutic agents, cytotoxicagents, or radiation. In one embodiment, the disorder is inflammatorydisease or immune disease, wherein the inflammatory disease or theimmune disease is selected from asthma, emphysema, allergy, dermatitis,rheumatoid arthritis, psoriasis, lupus erythematosus, graft versus hostdisease, inflammatory bowel disease, eczema, scleroderma, Crohn'sdisease, or multiple sclerosis. In one embodiment, the subject is amammal. In one embodiment, the mammal is a human. In one embodiment, thedisorder is rheumatoid arthritis, and the amount of the compound iseffective to ameliorate one or more symptoms associated with rheumatoidarthritis selected from one or more of a reduction in the swelling ofthe joints, a reduction in serum anti collagen levels, a reduction inbone resorption, a reduction in cartilage damage, a reduction in pannus,or a reduction in inflammation. In one embodiment, the respiratorydisease is chosen from asthma, chronic obstructive pulmonary disease(COPD), chronic bronchitis, emphysema, or bronchiectasis. In oneembodiment, the compound is administered in combination with an mTORinhibitor. In one embodiment, the compound is administered incombination with an agent chosen from one or more of: an agent thatinhibits IgE production or activity,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, an mTORinhibitor, rapamycin, a TORC1 inhibitor, a TORC2 inhibitor, an anti-IgEantibody, prednisone, corticosteroid, a leukotriene inhibitor, XOLAIR,ADVAIR, SINGULAIR, or SPIRIVA. In one embodiment, the compound isadministered in combination with one or more of: a mitotic inhibitor, analkylating agent, an anti-metabolite, an intercalating antibiotic, agrowth factor inhibitor, a cell cycle inhibitor, an enzyme, atopoisomerase inhibitor, an anti-hormone, an angiogenesis inhibitor, ananti-androgen, or an anti-receptor kinase antibody. In one embodiment,the compound is administered in combination with one or more of:Imatinib Mesylate, bortezomib, bicalutamide, gefitinib, ADRIAMYCIN,alkylating agents, alkyl sulfonates, ethylenimines, altretamine,triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide, trimethylolomelamine, nitrogen mustards,chlorambucil, chlornaphazine, cholophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard, nitrosureas, antibiotics, anti-metabolites, denopterin,methotrexate, pteropterin, trimetrexate, 5-fluorouracil (5-FU),fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine,azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,doxifluridine, enocitabine, floxuridine, androgens, anti-adrenals, folicacid replenisher, arabinoside, cyclophosphamide, thiotepa, taxanes,anti-hormonal agents, anti-estrogens, tamoxifen, raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,onapristone, toremifene, anti-androgens, chlorambucil, gemcitabine,6-thioguanine; mercaptopurine; cisplatin, carboplatin, vincristine;vinorelbine, vinblastin, ifosfamide, mitomycin C, daunorubicin,doxorubicin, mitoxantrone, HERCEPTIN, AVASTIN, ERBITUX, RITUXAN, TAXOL,ARIMIDEX, TAXOTERE, or an anti-receptor tyrosine kinase antibody chosenfrom cetuximab, panitumumab, trastuzumab, anti CD20 antibody, rituximab,tositumomab, alemtuzumab, bevacizumab, or gemtuzumab. In one embodiment,the compound is administered in combination with one or more of:non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids,prednisone, chloroquine, hydroxychloroquine, azathioprine,cyclophosphamide, methotrexate, cyclosporine, anti-CD20 antibodies,ENBREL, REMICADE, HUMIRA, AVONEX, or REBIF. In one embodiment, thecompound of Formula I is predominately in an (S)-stereochemicalconfiguration. In one embodiment, the compound of Formula I is the Senantiomer having an enantiomeric purity selected from greater thanabout 55%, greater than about 80%, greater than about 90%, and greaterthan about 95%. In one embodiment, the compound is present in apharmaceutical composition comprising the compound, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients. In one embodiment, the subjectis a human. In one embodiment, the disorder is rheumatoid arthritis. Inone embodiment, the disorder is asthma. In one embodiment, the disorderis cancer. In one embodiment, the compound is administered incombination with one or more of: a mitotic inhibitor, an alkylatingagent, an anti-metabolite, an intercalating antibiotic, a growth factorinhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor,an anti-hormone, an angiogenesis inhibitor, an anti-androgen, or ananti-receptor kinase antibody. In one embodiment, the compound isadministered in combination with an mTOR inhibitor. In one embodiment,the compound is administered in combination with an agent chosen fromone or more of: an agent that inhibits IgE production or activity,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, an mTORinhibitor, rapamycin, a TORC1 inhibitor, a TORC2 inhibitor, an anti-IgEantibody, prednisone, corticosteroid, a leukotriene inhibitor, XOLAIR,ADVAIR, SINGULAIR, or SPIRIVA. In one embodiment, the compound isadministered in combination with one or more of: Imatinib Mesylate,bortezomib, bicalutamide, gefitinib, ADRIAMYCIN, alkylating agents,alkyl sulfonates, ethylenimines, altretamine, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphaoramide,trimethylolomelamine, nitrogen mustards, chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard, nitrosureas,antibiotics, anti-metabolites, denopterin, methotrexate, pteropterin,trimetrexate, 5-fluorouracil (5-FU), fludarabine, 6-mercaptopurine,thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,floxuridine, androgens, anti-adrenals, folic acid replenisher,arabinoside, cyclophosphamide, thiotepa, taxanes, anti-hormonal agents,anti-estrogens, tamoxifen, raloxifene, aromatase inhibiting4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone,toremifene, anti-androgens, chlorambucil, gemcitabine, 6-thioguanine;mercaptopurine; cisplatin, carboplatin, vincristine; vinorelbine,vinblastin, ifosfamide, mitomycin C, daunorubicin, doxorubicin,mitoxantrone, HERCEPTIN, AVASTIN, ERBITUX, RITUXAN, TAXOL, ARIMIDEX,TAXOTERE, or an anti-receptor tyrosine kinase antibody chosen fromcetuximab, panitumumab, trastuzumab, anti CD20 antibody, rituximab,tositumomab, alemtuzumab, bevacizumab, or gemtuzumab. In one embodiment,the compound is administered in combination with one or more of:non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids,prednisone, chloroquine, hydroxychloroquine, azathioprine,cyclophosphamide, methotrexate, cyclosporine, anti-CD20 antibodies,ENBREL, REMICADE, HUMIRA, AVONEX, or REBIF. In one embodiment, themethod further comprises administration of one or more therapeuticagents selected from chemotherapeutic agents, cytotoxic agents, orradiation.

In one embodiment, provided herein is a method of inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) in a subject suffering froma cancer, comprising administering to the subject an effective amount ofa compound provided herein (e.g., a compound of Formula I).

In one embodiment, the cancer is selected from acute myeloid leukemia(AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS),myeloproliferative disorders, mast cell cancer, Hodgkin disease,non-Hodgkin lymphomas, diffuse large B-cell lymphoma, humanlymphotrophic virus-type 1 (HTLV-1) leukemia/lymphoma, AIDS-relatedlymphoma, adult T-cell lymphoma, acute lymphocytic leukemia (ALL),B-cell acute lymphoblastic leukemia, T-cell acute lymphoblasticleukemia, chronic lymphocytic leukemia, or multiple myeloma (MM). In oneembodiment, the cancer is leukemia or lymphoma. In one embodiment, theleukemia is selected from B-cell acute lymphoblastic leukemia (B-ALL),acute lymphocytic leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), multiplemyeloma (MM), myelodysplastic syndrome (MDS), or mast cell cancer. Inone embodiment, the lymphoma is selected from diffuse large B-celllymphoma, B-cell immunoblastic lymphoma, small non-cleaved celllymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma,AIDS-related lymphoma, adult T-cell lymphoma, Hodgkin disease, ornon-Hodgkin lymphomas.

In one embodiment, the compound is administered in combination with oneor more of: a mitotic inhibitor, an alkylating agent, ananti-metabolite, an intercalating antibiotic, a growth factor inhibitor,a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, ananti-hormone, an angiogenesis inhibitor, an anti-androgen, or ananti-receptor kinase antibody. In one embodiment, the compound isadministered in combination with one or more of: Imatinib Mesylate,bortezomib, bicalutamide, gefitinib, ADRIAMYCIN, alkylating agents,alkyl sulfonates, ethylenimines, altretamine, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphaoramide,trimethylolomelamine, nitrogen mustards, chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard, nitrosureas,antibiotics, anti-metabolites, denopterin, methotrexate, pteropterin,trimetrexate, 5-fluorouracil (5-FU), fludarabine, 6-mercaptopurine,thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,floxuridine, androgens, anti-adrenals, folic acid replenisher,arabinoside, cyclophosphamide, thiotepa, taxanes, anti-hormonal agents,anti-estrogens, tamoxifen, raloxifene, aromatase inhibiting4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone,toremifene, anti-androgens, chlorambucil, gemcitabine, 6-thioguanine;mercaptopurine; cisplatin, carboplatin, vincristine; vinorelbine,vinblastin, ifosfamide, mitomycin C, daunorubicin, doxorubicin,mitoxantrone, HERCEPTIN, AVASTIN, ERBITUX, RITUXAN, TAXOL, ARIMIDEX,TAXOTERE, or an anti-receptor tyrosine kinase antibody chosen fromcetuximab, panitumumab, trastuzumab, anti CD20 antibody, rituximab, tositumomab, alemtuzumab, bevacizumab, or gemtuzumab. In one embodiment,the compound is administered in combination with one or more of:bortezomib, ADRIAMYCIN, alkylating agents, anti-metabolites, denopterin,pteropterin, trimetrexate, a nitrogen mustard, chlorambucil,chlornaphazine, cholophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard,methotrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine,ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens,cyclophosphamide, taxanes, anti-hormonal agents, gemcitabine; cisplatin,carboplatin, vincristine, vinorelbine, vinblastin, ifosfamide, mitomycinC, daunorubicin, doxorubicin, mitoxantrone, HERCEPTIN, AVASTIN, ERBITUX,RITUXAN, TAXOL, ARIMIDEX, or TAXOTERE.

In one embodiment, provided herein is a method of inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) in a subject suffering froman inflammatory disease or an immune disease, comprising administeringto the subject an effective amount of a compound provided herein (e.g.,a compound of Formula I). In one embodiment, the inflammatory disease orimmune disease is selected from asthma, emphysema, allergy, dermatitis,rheumatoid arthritis, psoriasis, lupus erythematosus, graft versus hostdisease, inflammatory bowel disease, eczema, scleroderma, Crohn'sdisease, or multiple sclerosis. In one embodiment, the inflammatorydisease or immune disease is rheumatoid arthritis. In one embodiment,the compound is administered in combination with non-steroidalanti-inflammatory drugs (NSAIDs), corticosteroids, prednisone,chloroquine, hydroxychloroquine, azathioprine, cyclophosphamide,methotrexate, cyclosporine, anti-CD20 antibodies, ENBREL, REMICADE,HUMIRA, AVONEX, or REBIF.

In one embodiment, provided herein is a method of inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) in a subject suffering froma respiratory disease, comprising administering to the subject aneffective amount of a compound provided herein (e.g., a compound ofFormula I). In one embodiment, the respiratory disease is chosen fromasthma, chronic obstructive pulmonary disease (COPD), chronicbronchitis, emphysema, or bronchiectasis. In one embodiment, therespiratory disease is asthma. In one embodiment, the compound isadministered in combination with one or more of: an agent that inhibitsIgE production or activity,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, an mTORinhibitor, rapamycin, a TORC1 inhibitor, a TORC2 inhibitor, an anti-IgEantibody, prednisone, corticosteroid, a leukotriene inhibitor, XOLAIR,ADVAIR, SINGULAIR, or SPIRIVA.

In certain embodiments, provided herein is a method of inhibiting PI3K-γin a subject, comprising administering to the subject an effectiveamount of a compound provided herein (e.g., a compound of Formula I).

In certain embodiments, provided herein is a method of inhibiting PI3K-δin a subject, comprising administering to the subject an effectiveamount of a compound provided herein (e.g., a compound of Formula I).

In some embodiments, provided herein is a method of making a compound asdescribed herein.

In certain embodiments, provided herein is a reaction mixture comprisinga compound as described herein.

In certain embodiments, provided herein is a kit comprising a compoundas described herein.

In some embodiments, a method is provided for treating a disease ordisorder described herein, the method comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein to a subject.

In some embodiments, a method is provided for treating a PI3K mediateddisorder in a subject, the method comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein to a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein for the treatment of adisease or disorder described herein in a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein for the treatment of a PI3Kmediated disorder in a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein in the manufacture of amedicament for the treatment of a disease or disorder described hereinin a subject.

In certain embodiments, provided herein is use of a compound or apharmaceutical composition described herein in the manufacture of amedicament for the treatment of a PI3K mediated disorder in a subject.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.In case of conflict, the present application, including any definitionsherein, will control.

DETAILED DESCRIPTION

In one embodiment, provided are heterocyclyl compounds, andpharmaceutically acceptable forms, including, but not limited to, salts,hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives thereof.

In another embodiment, provided are methods of treating and/or managingvarious diseases and disorders, which comprises administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof. Examples of diseases and disorders are described herein.

In another embodiment, provided are methods of preventing variousdiseases and disorders, which comprises administering to a patient inneed of such prevention a prophylactically effective amount of acompound provided herein, or a pharmaceutically acceptable form (e.g.,salts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. Examples of diseases and disorders are describedherein.

In other embodiments, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, is administered incombination with another drug (“second active agent”) or treatment.Second active agents include small molecules and large molecules (e.g.,proteins and antibodies), examples of which are provided herein, as wellas stem cells. Other methods or therapies that can be used incombination with the administration of compounds provided hereininclude, but are not limited to, surgery, blood transfusions,immunotherapy, biological therapy, radiation therapy, and other non-drugbased therapies presently used to treat, prevent or manage variousdisorders described herein.

Also provided are pharmaceutical compositions (e.g., single unit dosageforms) that can be used in the methods provided herein. In oneembodiment, pharmaceutical compositions comprise a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, and optionally one or more second active agents.

While specific embodiments have been discussed, the specification isillustrative only and not restrictive. Many variations of thisdisclosure will become apparent to those skilled in the art upon reviewof this specification.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this specification pertains.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

As used herein, and unless otherwise indicated, the term “about” or“approximately” means an acceptable error for a particular value asdetermined by one of ordinary skill in the art, which depends in part onhow the value is measured or determined. In certain embodiments, theterm “about” or “approximately” means within 1, 2, 3, or 4 standarddeviations. In certain embodiments, the term “about” or “approximately”means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.5%, or 0.05% of a given value or range.

As used herein, “agent” or “biologically active agent” or “second activeagent” refers to a biological, pharmaceutical, or chemical compound orother moiety. Non-limiting examples include simple or complex organic orinorganic molecules, a peptide, a protein, an oligonucleotide, anantibody, an antibody derivative, an antibody fragment, a vitamin, avitamin derivative, a carbohydrate, a toxin, or a chemotherapeuticcompound, and metabolites thereof. Various compounds can be synthesized,for example, small molecules and oligomers (e.g., oligopeptides andoligonucleotides), and synthetic organic compounds based on various corestructures. In addition, various natural sources can provide compoundsfor screening, such as plant or animal extracts, and the like. A skilledartisan can readily recognize that there is no limit as to thestructural nature of the agents of this disclosure.

The term “agonist” as used herein refers to a compound or agent havingthe ability to initiate or enhance a biological function of a targetprotein or polypeptide, such as increasing the activity or expression ofthe target protein or polypeptide. Accordingly, the term “agonist” isdefined in the context of the biological role of the target protein orpolypeptide. While some agonists herein specifically interact with(e.g., bind to) the target, compounds and/or agents that initiate orenhance a biological activity of the target protein or polypeptide byinteracting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound or agent having the ability to inhibit abiological function of a target protein or polypeptide, such as byinhibiting the activity or expression of the target protein orpolypeptide. Accordingly, the terms “antagonist” and “inhibitor” aredefined in the context of the biological role of the target protein orpolypeptide. While some antagonists herein specifically interact with(e.g., bind to) the target, compounds that inhibit a biological activityof the target protein or polypeptide by interacting with other membersof the signal transduction pathway of which the target protein orpolypeptide are also specifically included within this definition.Non-limiting examples of biological activity inhibited by an antagonistinclude those associated with the development, growth, or spread of atumor, or an undesired immune response as manifested in autoimmunedisease.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, or buccal administration, orinhalation, or in the form of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to subject so that both agents and/or theirmetabolites are present in the subject at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or pharmaceutical composition describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment, as illustrated below. Thetherapeutically effective amount can vary depending upon the intendedapplication (in vitro or in vivo), or the subject and disease conditionbeing treated, e.g., the weight and age of the subject, the severity ofthe disease condition, the manner of administration and the like, whichcan readily be determined by one of ordinary skill in the art. The termalso applies to a dose that will induce a particular response in targetcells, e.g., reduction of platelet adhesion and/or cell migration. Thespecific dose will vary depending on, for example, the particularcompounds chosen, the dosing regimen to be followed, whether it isadministered in combination with other agents, timing of administration,the tissue to which it is administered, and the physical delivery systemin which it is carried.

As used herein, the terms “treatment”, “treating”, “palliating” and“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including, but notlimited to, therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient can still be afflicted with the underlying disorder. Forprophylactic benefit, the pharmaceutical compositions can beadministered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A “modulator” of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator can augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or interact interaction with the target. Forexample, a compound that selectively inhibits one isoform of PI3K overanother isoform of PI3K has an activity of at least 2× against a firstisoform relative to the compound's activity against the second isoform(e.g., at least about 3×, 5×, 10×, 20×, 50×, 100×, 200×, 500×, or1000×).

“Radiation therapy” means exposing a patient, using routine methods andcompositions known to the practitioner, to radiation emitters such as,but not limited to, alpha-particle emitting radionuclides (e.g.,actinium and thorium radionuclides), low linear energy transfer (LET)radiation emitters (e.g., beta emitters), conversion electron emitters(e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation,including without limitation x-rays, gamma rays, and neutrons.

“Subject” to which administration is contemplated includes, but is notlimited to, humans (e.g., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, quail, and/or turkeys.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assayconducted outside of a subject. In vitro assays encompass cell-basedassays in which cells, alive or dead, are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

As used herein, “pharmaceutically acceptable esters” include, but arenot limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkylesters of acidic groups, including, but not limited to, carboxylicacids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinicacids, and boronic acids.

As used herein, “pharmaceutically acceptable enol ethers” include, butare not limited to, derivatives of formula —C═C(OR) where R can beselected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl.Pharmaceutically acceptable enol esters include, but are not limited to,derivatives of formula —C═C(OC(O)R) where R can be selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl.

As used herein, a “pharmaceutically acceptable form” of a disclosedcompound includes, but is not limited to, pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives of disclosed compounds. In one embodiment, a“pharmaceutically acceptable form” includes, but is not limited to,pharmaceutically acceptable salts, isomers, prodrugs and isotopicallylabeled derivatives of disclosed compounds.

In certain embodiments, the pharmaceutically acceptable form is apharmaceutically acceptable salt. As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of subjects without undue toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, Berge et al. describes pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.Pharmaceutically acceptable salts of the compounds provided hereininclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate,laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. In some embodiments, organic acids from which salts can be derivedinclude, for example, acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, andaryl sulfonate. Organic bases from which salts can be derived include,for example, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, basicion exchange resins, and the like, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts.

In certain embodiments, the pharmaceutically acceptable form is asolvate (e.g., a hydrate). As used herein, the term “solvate” refers tocompounds that further include a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Thesolvate can be of a disclosed compound or a pharmaceutically acceptablesalt thereof. Where the solvent is water, the solvate is a “hydrate”.Pharmaceutically acceptable solvates and hydrates are complexes that,for example, can include 1 to about 100, or 1 to about 10, or one toabout 2, about 3 or about 4, solvent or water molecules. It will beunderstood that the term “compound” as used herein encompasses thecompound and solvates of the compound, as well as mixtures thereof.

In certain embodiments, the pharmaceutically acceptable form is aprodrug. As used herein, the term “prodrug” refers to compounds that aretransformed in vivo to yield a disclosed compound or a pharmaceuticallyacceptable form of the compound. A prodrug can be inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis (e.g., hydrolysis in blood). Incertain cases, a prodrug has improved physical and/or deliveryproperties over the parent compound. Prodrugs are typically designed toenhance pharmaceutically and/or pharmacokinetically based propertiesassociated with the parent compound. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs isprovided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,”A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated in full byreference herein. Exemplary advantages of a prodrug can include, but arenot limited to, its physical properties, such as enhanced watersolubility for parenteral administration at physiological pH compared tothe parent compound, or it enhances absorption from the digestive tract,or it can enhance drug stability for long-term storage.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a subject. Prodrugs of an active compound, as describedherein, can be prepared by modifying functional groups present in theactive compound in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds wherein a hydroxy, amino or mercapto group isbonded to any group that, when the prodrug of the active compound isadministered to a subject, cleaves to form a free hydroxy, free amino orfree mercapto group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of an alcoholor acetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like. Other examples of prodrugsinclude compounds that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described in Burger's Medicinal Chemistry and Drug Discovery,172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design ofProdrugs (H. Bundgaard ed., Elsevier, New York, 1985).

For example, if a disclosed compound or a pharmaceutically acceptableform of the compound contains a carboxylic acid functional group, aprodrug can comprise a pharmaceutically acceptable ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as (3-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a disclosed compound or a pharmaceutically acceptable formof the compound contains an alcohol functional group, a prodrug can beformed by the replacement of the hydrogen atom of the alcohol group witha group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂, and glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a disclosed compound or a pharmaceutically acceptable form of thecompound incorporates an amine functional group, a prodrug can be formedby the replacement of a hydrogen atom in the amine group with a groupsuch as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY¹wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ wherein Y² is(C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N— or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵wherein Y⁴ is H or methyl and Y⁵ is mono-N— or di-N,N—(C₁-C₆)alkylamino,morpholino, piperidin-1-yl or pyrrolidin-1-yl.

In certain embodiments, the pharmaceutically acceptable form is anisomer. “Isomers” are different compounds that have the same molecularformula. “Stereoisomers” are isomers that differ only in the way theatoms are arranged in space. As used herein, the term “isomer” includesany and all geometric isomers and stereoisomers. For example, “isomers”include geometric double bond cis- and trans-isomers, also termed E- andZ-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and(l)-isomers, racemic mixtures thereof; and other mixtures thereof, asfalling within the scope of this disclosure.

In certain embodiments, the symbol

denotes a bond that can be a single or double as described herein.

In certain embodiments, provided herein are various geometric isomersand mixtures thereof resulting from the arrangement of substituentsaround a carbon-carbon double bond or arrangement of substituents arounda carbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring can also be designated as “cis” or “trans.”The term “cis” represents substituents on the same side of the plane ofthe ring, and the term “trans” represents substituents on opposite sidesof the plane of the ring. Mixtures of compounds wherein the substituentsare disposed on both the same and opposite sides of the plane of thering are designated “cis/trans.”

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A mixture of a pair of enantiomers in anyproportion can be known as a “racemic” mixture. The term “(±)” is usedto designate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry can bespecified according to the Cahn-Ingold-Prelog R-S system. When acompound is an enantiomer, the stereochemistry at each chiral carbon canbe specified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers and can thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat can be defined, in terms of absolute stereochemistry at eachasymmetric atom, as (R)- or (S)-. The present chemical entities,pharmaceutical compositions and methods are meant to include all suchpossible isomers, including racemic mixtures, optically substantiallypure forms and intermediate mixtures. Optically active (R)- and(S)-isomers can be prepared, for example, using chiral synthons orchiral reagents, or resolved using conventional techniques.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow, a composition contains 90% of one enantiomer, e.g., an Senantiomer, and 10% of the other enantiomer, e.g., an R enantiomer.ee=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%. Somecompositions described herein contain an enantiomeric excess of at leastabout 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about50%, about 75%, about 90%, about 95%, or about 99% of the S enantiomer.In other words, the compositions contain an enantiomeric excess of the Senantiomer over the R enantiomer. In other embodiments, somecompositions described herein contain an enantiomeric excess of at leastabout 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about50%, about 75%, about 90%, about 95%, or about 99% of the R enantiomer.In other words, the compositions contain an enantiomeric excess of the Renantiomer over the S enantiomer.

For instance, an isomer/enantiomer can, in some embodiments, be providedsubstantially free of the corresponding enantiomer, and can also bereferred to as “optically enriched,” “enantiomerically enriched,”“enantiomerically pure” and “non-racemic,” as used interchangeablyherein. These terms refer to compositions in which the amount of oneenantiomer is greater than the amount of that one enantiomer in acontrol mixture of the racemic composition (e.g., greater than 1:1 byweight). For example, an enantiomerically enriched preparation of the Senantiomer, means a preparation of the compound having greater thanabout 50% by weight of the S enantiomer relative to the total weight ofthe preparation (e.g., total weight of S and R isomers). such as atleast about 75% by weight, further such as at least about 80% by weight.In some embodiments, the enrichment can be much greater than about 80%by weight, providing a “substantially enantiomerically enriched,”“substantially enantiomerically pure” or a “substantially non-racemic”preparation, which refers to preparations of compositions which have atleast about 85% by weight of one enantiomer relative to the total weightof the preparation, such as at least about 90% by weight, and furthersuch as at least about 95% by weight. In certain embodiments, thecompound provided herein is made up of at least about 90% by weight ofone enantiomer. In other embodiments, the compound is made up of atleast about 95%, about 98%, or about 99% by weight of one enantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, insome embodiments, the compound mixture has an (S)-enantiomeric excess ofgreater than about 10%, greater than about 20%, greater than about 30%,greater than about 40%, greater than about 50%, greater than about 55%,greater than about 60%, greater than about 65%, greater than about 70%,greater than about 75%, greater than about 80%, greater than about 85%,greater than about 90%, greater than about 95%, greater than about 96%,greater than about 97%, greater than about 98%, or greater than about99%. In some embodiments, the compound mixture has an (S)-enantiomericexcess of about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%,about 99%, or about 99.5%, or more. In some embodiments, the compoundmixture has an (S)-enantiomeric excess of about 55% to about 99.5%,about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% toabout 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%,or about 99% to about 99.5%, or more than about 99.5%.

In other embodiments, the compound mixture has an (R)-enantiomericexcess of greater than about 10%, greater than about 20%, greater thanabout 30%, greater than about 40%, greater than about 50%, greater thanabout 55%, greater than about 60%, greater than about 65%, greater thanabout 70%, greater than about 75%, greater than about 80%, greater thanabout 85%, greater than about 90%, greater than about 95%, greater thanabout 96%, greater than about 97%, greater than about 98%, or greaterthan about 99%. In some embodiments, the compound mixture has an(R)-enantiomeric excess of about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about97%, about 98%, about 99%, or about 99.5%, or more. In some embodiments,the compound mixture has an (R)-enantiomeric excess of about 55% toabout 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%,about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% toabout 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

In other embodiments, the compound mixture contains identical chemicalentities except for their stereochemical orientations, namely (S)- or(R)-isomers. For example, if a compound disclosed herein has —CH(R)—unit, and R is not hydrogen, then the —CH(R)— is in an (S)- or(R)-stereochemical orientation for each of the identical chemicalentities (i.e., (S)- or (R)-stereoisomers). In some embodiments, themixture of identical chemical entities (i.e., mixture of stereoisomers)is a racemic mixture of (S)- and (R)-isomers. In another embodiment, themixture of the identical chemical entities (i.e., mixture ofstereoisomers) contains predominately (S)-isomer or predominately(R)-isomer. For example, in some embodiments, the (S)-isomer in themixture of identical chemical entities (i.e., mixture of stereoisomers)is present at about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, about 99%, or about 99.5% by weight, or more, relative to the totalweight of the mixture of (S)- and (R)-isomers. In some embodiments, the(S)-isomer in the mixture of identical chemical entities (i.e., mixtureof stereoisomers) is present at an (S)-enantiomeric excess of about 10%to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%,about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% toabout 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%,about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about99.5%, or about 99% to about 99.5%, or more than about 99.5%.

In other embodiments, the (R)-isomer in the mixture of identicalchemical entities (i.e., mixture of stereoisomers) is present at about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, orabout 99.5% by weight, or more, relative to the total weight of themixture of (S)- and (R)-isomers. In some embodiments, the (R)-isomers inthe mixture of identical chemical entities (i.e., mixture ofstereoisomers) is present at an (R)-enantiomeric excess of about 10% toabout 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%,about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% toabout 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%,or about 99% to about 99.5%, or more than about 99.5%.

Enantiomers can be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC), the formation and crystallization of chiralsalts, or prepared by asymmetric syntheses. See, for example,Enantiomers, Racemates and Resolutions (Jacques, Ed., WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Stereochemistry of Carbon Compounds (E. L. Eliel, Ed., McGraw-Hill, NY,1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

In certain embodiments, the pharmaceutically acceptable form is atautomer. As used herein, the term “tautomer” is a type of isomer thatincludes two or more interconvertable compounds resulting from at leastone formal migration of a hydrogen atom and at least one change invalency (e.g., a single bond to a double bond, a triple bond to a doublebond, or a triple bond to a single bond, or vice versa).“Tautomerization” includes prototropic or proton-shift tautomerization,which is considered a subset of acid-base chemistry. “Prototropictautomerization” or “proton-shift tautomerization” involves themigration of a proton accompanied by changes in bond order. The exactratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Where tautomerization is possible (e.g.,in solution), a chemical equilibrium of tautomers can be reached.Tautomerizations (i.e., the reaction providing a tautomeric pair) can becatalyzed by acid or base, or can occur without the action or presenceof an external agent. Exemplary tautomerizations include, but are notlimited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; andenamine-(a different) enamine tautomerizations. A specific example ofketo-enol tautomerization is the interconversion of pentane-2,4-dioneand 4-hydroxypent-3-en-2-one tautomers. Another example oftautomerization is phenol-keto tautomerization. A specific example ofphenol-keto tautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement or enrichment of a hydrogen bydeuterium or tritium, or the replacement or enrichment of a carbon by¹³C or ¹⁴C, are within the scope of this disclosure.

The disclosure also embraces isotopically labeled compounds which areidentical to those recited herein, except that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into disclosed compounds includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur,fluorine, and chlorine, such as, e.g., ²H, ³H, ¹³H, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Certain isotopically-labeleddisclosed compounds (e.g., those labeled with ³H and/or ¹⁴C) are usefulin compound and/or substrate tissue distribution assays. Tritiated(i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can allow for ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) can afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements). Isotopically labeleddisclosed compounds can generally be prepared by substituting anisotopically labeled reagent for a non-isotopically labeled reagent. Insome embodiments, provided herein are compounds that can also containunnatural proportions of atomic isotopes at one or more of atoms thatconstitute such compounds. All isotopic variations of the compounds asdisclosed herein, whether radioactive or not, are encompassed within thescope of the present disclosure.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions as disclosedherein is contemplated. Supplementary active ingredients can also beincorporated into the pharmaceutical compositions.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th ed., inside cover, and specificfunctional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5th ed., John Wiley& Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge UniversityPress, Cambridge, 1987.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having, in some embodiments, from one to ten carbon atoms(e.g., C₁-C₁₀ alkyl). Whenever it appears herein, a numerical range suchas “1 to 10” refers to each integer in the given range; e.g., “1 to 10carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including10 carbon atoms, although the present definition also covers theoccurrence of the term “alkyl” where no numerical range is designated.In some embodiments, an alkyl is a C₁-C₆ alkyl group. In someembodiments, alkyl groups have 1 to 10, 1 to 6, 1 to 4, or 1 to 3 carbonatoms. Representative saturated straight chain alkyls include, but arenot limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and-n-hexyl; while saturated branched alkyls include, but are not limitedto, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl,2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached tothe parent molecule by a single bond. Unless stated otherwise in thespecification, an alkyl group is optionally substituted by one or moreof substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfonyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂, where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Perhaloalkyl” refers to an alkyl group in which all of the hydrogenatoms have been replaced with a halogen selected from fluoro, chloro,bromo, and iodo. In some embodiments, all of the hydrogen atoms are eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like. “Haloalkyl”refers to an alkyl group in which one or more of the hydrogen atoms havebeen replaced with a halogen independently selected from fluoro, chloro,bromo, and iodo.

“Alkyl-cycloalkyl” refers to an -(alkyl)cycloalkyl radical where alkyland cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkyl and cycloalkyl respectively. The“alkyl-cycloalkyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “alkenyl-cycloalkyl” and “alkynyl-cycloalkyl”mirror the above description of “alkyl-cycloalkyl” wherein the term“alkyl” is replaced with “alkenyl” or “alkynyl” respectively, and“alkenyl” or “alkynyl” are as described herein.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas disclosed herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively. The “alkylaryl” is bonded to the parent molecularstructure through the alkyl group. The terms “-(alkenyl)aryl” and“-(alkynyl)aryl” mirror the above description of “-(alkyl)aryl” whereinthe term “alkyl” is replaced with “alkenyl” or “alkynyl” respectively,and “alkenyl” or “alkynyl” are as described herein.

“Alkyl-heteroaryl” refers to an -(alkyl)heteroaryl radical whereheteroaryl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The“alkyl-heteroaryl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heteroaryl” and“-(alkynyl)heteroaryl” mirror the above description of“-(alkyl)heteroaryl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Alkyl-heterocyclyl” refers to an (alkyl)heterocyclyl radical wherealkyl and heterocyclyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“alkyl-heterocyclyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heterocyclyl” and“-(alkynyl)heterocyclyl” mirror the above description of“-(alkyl)heterocyclyl” wherein the term “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and “alkenyl” or “alkynyl” are asdescribed herein.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and in some embodiments, having from two to tencarbon atoms (i.e., C₂-C₁₀ alkenyl). Whenever it appears herein, anumerical range such as “2 to 10” refers to each integer in the givenrange; e.g., “2 to 10 carbon atoms” means that the alkenyl group canconsist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up toand including 10 carbon atoms. In certain embodiments, an alkenylcomprises two to eight carbon atoms. In other embodiments, an alkenylcomprises two to five carbon atoms (e.g., C₂-C₅ alkenyl). The alkenyl isattached to the parent molecular structure by a single bond, forexample, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. The one or morecarbon-carbon double bonds can be internal (such as in 2-butenyl) orterminal (such as in 1-butenyl). Examples of C₂₋₄ alkenyl groups includeethenyl (C₂₋), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄),2-butenyl (C₄), butadienyl (C₄) and the like. Examples of C₂₋₆ alkenylgroups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless stated otherwise in the specification, analkenyl group is optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfonyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or OP(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having, in some embodiments, from two to tencarbon atoms (i.e., C₂-C₁₀ alkynyl). Whenever it appears herein, anumerical range such as “2 to 10” refers to each integer in the givenrange; e.g., “2 to 10 carbon atoms” means that the alkynyl group canconsist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up toand including 10 carbon atoms. In certain embodiments, an alkynylcomprises two to eight carbon atoms. In other embodiments, an alkynylhas two to five carbon atoms (e.g., C₂-C₅ alkynyl). The alkynyl isattached to the parent molecular structure by a single bond, forexample, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.Unless stated otherwise in the specification, an alkynyl group isoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, Si(R^(a))₃, —OR^(a), SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or OP(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “alkoxy” refers to the group —O-alkyl (in some embodiments,including from 1 to 10 carbon atoms), of a straight, branched, cyclicconfiguration and combinations thereof, attached to the parent molecularstructure through an oxygen. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. “Lower alkoxy”refers to alkoxy groups containing one to six carbons. In someembodiments, C₁-C₄ alkoxy is an alkoxy group which encompasses bothstraight and branched chain alkyls of from 1 to 4 carbon atoms. Unlessstated otherwise in the specification, an alkoxy group is optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxy” and “alkynoxy” mirror the above description of “alkoxy”wherein the prefix “alk” is replaced with “alken” or “alkyn”respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached to the parent molecular structure through thecarbonyl carbon (in some embodiments, having from 1 to 10 carbon atoms).Thus a C₁-C₆ alkoxycarbonyl group comprises an alkoxy group having from1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.The C₁-C₆ designation does not include the carbonyl carbon in the atomcount. “Lower alkoxycarbonyl” refers to an alkoxycarbonyl group whereinthe alkyl portion of the alkoxy group is a lower alkyl group. In someembodiments, C₁-C₄ alkoxycarbonyl comprises an alkoxy group whichencompasses both straight and branched chain alkoxy groups of from 1 to4 carbon atoms. Unless stated otherwise in the specification, analkoxycarbonyl group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxycarbonyl” and “alkynoxycarbonyl” mirror the above descriptionof “alkoxycarbonyl” wherein the prefix “alk” is replaced with “alken” or“alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

“Acyl” refers to R—C(O)— groups such as, but not limited to, H,(alkyl)-C(O)—, (alkenyl)-C(O)—, (alkynyl)-C(O)—, (aryl)-C(O)—,(cycloalkyl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentmolecular structure through the carbonyl functionality. In someembodiments, provided herein is a C₁-C₁₀ acyl radical which refers tothe total number of chain or ring atoms of the, for example, alkyl,alkenyl, alkynyl, aryl, cyclohexyl, heteroaryl or heterocycloalkylportion plus the carbonyl carbon of acyl. For example, a C₄-acyl hasthree other ring or chain atoms plus carbonyl. If the R radical isheteroaryl or heterocycloalkyl, the hetero ring or chain atomscontribute to the total number of chain or ring atoms. Unless statedotherwise in the specification, the “R” of an acyloxy group can beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Acyloxy” refers to a R(C═O)O— radical wherein “R” can be H, alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,cyclohexyl, heteroaryl, or heterocycloalkyl, which are as describedherein. The acyloxy group is attached to the parent molecular structurethrough the oxygen functionality. In some embodiments, an acyloxy groupis a C₁-C₄ acyloxy radical which refers to the total number of chain orring atoms of the alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroarylor heterocycloalkyl portion of the acyloxy group plus the carbonylcarbon of acyl, e.g., a C₄-acyloxy has three other ring or chain atomsplus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, thehetero ring or chain atoms contribute to the total number of chain orring atoms. Unless stated otherwise in the specification, the “R” of anacyloxy group is optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Amino” or “amine” refers to a —N(R^(b))₂, —N(R^(b))R^(b)—, or—R^(b)N(R^(b))R^(b)— radical group, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon), andheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.When a —N(R^(b))₂ group has two R^(b) other than hydrogen, they can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, 7-, or8-membered ring. For example, —N(R^(b))₂ is meant to include, but not belimited to, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise inthe specification, an amino group is optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂, where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

The terms “amine” and “amino” can also refer to N-oxides of the groups—N⁺(H)(R^(a))O⁻, and —N⁺(R^(a))(R^(a))O⁻, where R^(a) is as describedabove, where the N-oxide is bonded to the parent molecular structurethrough the N atom. N-oxides can be prepared by treatment of thecorresponding amino group with, for example, hydrogen peroxide orm-chloroperoxybenzoic acid. The person skilled in the art is familiarwith reaction conditions for carrying out the N-oxidation.

“Amide” or “amido” refers to a chemical moiety with formula—C(O)N(R^(b))₂ or —NR^(b)C(O)R^(b), where R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon), andheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.In some embodiments, an amido or amide radical is a C₁-C₄ amido or amideradical, which includes the amide carbonyl in the total number ofcarbons in the radical. When a —C(O)N(R^(b))₂ has two R^(b) other thanhydrogen, they can be combined with the nitrogen atom to form a 3-, 4-,5-, 6-, 7-, or 8-membered ring. For example, N(R^(b))₂ portion of a—C(O)N(R^(b))₂ radical is meant to include, but not be limited to,1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise in thespecification, an amido R^(b) group is optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(A), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂, where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

The term “amide” or “amido” is inclusive of an amino acid or a peptidemolecule. Any amine, hydroxy, or carboxyl side chain on the compoundsdescribed herein can be transformed into an amide group. The proceduresand specific groups to make such amides are known to those of skill inthe art and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 4th Ed., John Wiley &Sons, New York, N.Y., 2006, which is incorporated herein by reference inits entirety.

“Amidino” refers to the —C(═NR^(b))N(R^(b))₂,—N(R^(b))—C(═NR^(b))—R^(b), and —N(R^(b))—C(═NR^(b))— radicals, whereeach R^(b) is independently selected from hydrogen, alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl (bonded through a chain carbon),cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bondedthrough a ring carbon), heterocycloalkylalkyl, heteroaryl (bondedthrough a ring carbon), and heteroarylalkyl, unless stated otherwise inthe specification, each of which moiety can itself be optionallysubstituted as described herein.

“Aryl” refers to a radical with six to fourteen ring atoms (e.g., C₆-C₁₄or C₆-C₁₀ aryl) which has at least one carbocyclic ring having aconjugated pi electron system which is aromatic (e.g., having 6, 10, or14 it electrons shared in a cyclic array) (e.g., phenyl, fluorenyl, andnaphthyl). In one embodiment, bivalent radicals formed from substitutedbenzene derivatives and having the free valences at ring atoms are namedas substituted phenylene radicals. In other embodiments, bivalentradicals derived from univalent monocyclic or polycyclic hydrocarbonradicals whose names end in “-yl” by removal of one hydrogen atom fromthe carbon atom with the free valence are named by adding “-idene” tothe name of the corresponding univalent radical, e.g., a naphthyl groupwith two points of attachment is termed naphthylidene. Whenever itappears herein, a numerical range such as “6 to 10 aryl” refers to eachinteger in the given range; e.g., “6 to 10 ring atoms” means that thearyl group can consist of 6 ring atoms, 7 ring atoms, etc., up to andincluding 10 ring atoms. The term includes monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of ring atoms)groups. Unless stated otherwise in the specification, an aryl moiety canbe optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. In oneembodiment, unless stated otherwise, “aryl” also includes ring systemswherein the aryl ring, as defined above, is fused with one or morecycloalkyl or heterocyclyl groups wherein the point of attachment to theparent molecular structure is on the aryl ring.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively. The “aralkyl” or “arylalkyl” is bonded tothe parent molecular structure through the alkyl group. The terms“aralkenyl/arylalkenyl” and “aralkynyl/arylalkynyl” mirror the abovedescription of “aralkyl/arylalkyl” wherein the “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and the “alkenyl” or “alkynyl”terms are as described herein.

“Azide” refers to a —N₃ radical.

“Carbamate” refers to any of the following radicals: —O—(C═O)N(R^(b)),—O—(C═O)N(R^(b))₂, —N(R^(b))—(C═O)—O—, and —N(R^(b))—(C═O)—OR^(b),wherein each R^(b) is independently selected from H, alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl (bonded through a chain carbon),cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bondedthrough a ring carbon), heterocycloalkylalkyl, heteroaryl (bondedthrough a ring carbon), and heteroarylalkyl, unless stated otherwise inthe specification, each of which moiety can itself be optionallysubstituted as described herein.

“Carbonate” refers to a —O—(C═O)—O— or —O—(C═O)—OR radical, where R canbe hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, aryl, cyclohexyl, heteroaryl, or heterocycloalkyl, whichare as described herein.

“Carbonyl” refers to a —(C═O)— radical.

“Carboxaldehyde” refers to a —(C═O)H— radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl,” or alternatively, “carbocyclyl,” refers to a monocyclic orpolycyclic radical that contains only carbon and hydrogen, and can besaturated or partially unsaturated. Partially unsaturated cycloalkylgroups can be termed “cycloalkenyl” if the carbocycle contains at leastone double bond, or “cycloalkynyl” if the carbocycle contains at leastone triple bond. Cycloalkyl groups include groups having from 3 to 10ring atoms (e.g., C₃-C₁₀ cyclo alkyl). Whenever it appears herein, anumerical range such as “3 to 10” refers to each integer in the givenrange; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group canconsist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up toand including 10 carbon atoms. The term “cycloalkyl” also includesbridged and spiro-fused cyclic structures containing no heteroatoms. Theterm also includes monocyclic or fused-ring polycyclic (i.e., ringswhich share adjacent pairs of ring atoms) groups. In some embodiments,it is a C₃-C₈ cycloalkyl radical. In some embodiments, it is a C₃-C₅cycloalkyl radical. Illustrative examples of cycloalkyl groups include,but are not limited to the following moieties: C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclobutyl (C₄),cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl(C₆), cyclohexadienyl (C₆), and the like. Examples of C₃₋₈ carbocyclylgroups include the aforementioned C₃₋₆ carbocyclyl groups as well ascycloheptyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and thelike. Examples of C₃₋₁₀ carbocyclyl groups include the aforementionedC₃₋₈ carbocyclyl groups as well as octahydro-1H-indenyl,decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless statedotherwise in the specification, a cycloalkyl group is optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. In oneembodiment, unless stated otherwise, “cycloalkyl” or “carbocyclyl” alsoincludes ring systems wherein the cycloalkyl or carbocyclyl ring, asdefined above, is fused with one or more aryl or heteroaryl groupswherein the point of attachment to the parent molecular structure is onthe cycloalkyl or carbocyclyl ring.

“Cycloalkyl-alkyl” refers to a (cycloalkyl)alkyl radical wherecycloalkyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkyl respectively. The“cycloalkyl-alkyl” is bonded to the parent molecular structure throughthe cycloalkyl group. The terms “cycloalkyl-alkenyl” and“cycloalkyl-alkynyl” mirror the above description of “cycloalkyl-alkyl”wherein the term “alkyl” is replaced with “alkenyl” or “alkynyl”respectively, and “alkenyl” or “alkynyl” are as described herein.

“Cycloalkyl-heterocycloalkyl” refers to a (cycloalkyl)heterocyclylalkylradical where cycloalkyl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heterocycloalkyl and cycloalkylrespectively. The “cycloalkyl-heterocycloalkyl” is bonded to the parentmolecular structure through the cycloalkyl group.

“Cycloalkyl-heteroaryl” refers to a (cycloalkyl)heteroaryl radical wherecycloalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“cycloalkyl-heteroaryl” is bonded to the parent molecular structurethrough the cycloalkyl group.

As used herein, a “covalent bond” or “direct bond” refers to a singlebond joining two groups.

“Ester” refers to a radical of formula —COOR, where R is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon), and heteroarylalkyl. Any amine, hydroxy,or carboxyl side chain on the compounds described herein can beesterified. The procedures and specific groups to make such esters areknown to those of skill in the art and can readily be found in referencesources such as Greene and Wuts, Protective Groups in Organic Synthesis,4th Ed., John Wiley & Sons, New York, N.Y., 2006, which is incorporatedherein by reference in its entirety. Unless stated otherwise in thespecification, an ester group can be optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂, where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Ether” refers to a —R^(b)—O—R^(b) radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro,bromo, or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine, such as, but not limited to, trifluoromethyl, difluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Eachof the alkyl, alkenyl, alkynyl and alkoxy groups are as defined hereinand can be optionally further substituted as defined herein.

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include alkyl,alkenyl and alkynyl radicals, respectively, which have one or moreskeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, and phosphorus, or combinations thereof. Anumerical range can be given, e.g., C₁-C₄ heteroalkyl which refers tothe chain length in total, which in this example can be up to 4 atomslong. For example, a —CH₂OCH₂CH₃ radical is referred to as a “C₄”heteroalkyl, which includes the heteroatom center in the atom chainlength description. Connection to the parent molecular structure can bethrough either a heteroatom or a carbon in the heteroalkyl chain. Forexample, an N-containing heteroalkyl moiety refers to a group in whichat least one of the skeletal atoms is a nitrogen atom. One or moreheteroatom(s) in the heteroalkyl radical can be optionally oxidized. Oneor more nitrogen atoms, if present, can also be optionally quaternized.For example, heteroalkyl also includes skeletal chains substituted withone or more nitrogen oxide (—O—) substituents. Exemplary heteroalkylgroups include, without limitation, ethers such as methoxyethanyl(—CH₂CH₂OCH₃), ethoxymethanyl (—CH₂OCH₂CH₃), (methoxymethoxy)ethanyl(—CH₂CH₂—OCH₂OCH₃), (methoxymethoxy)methanyl (—CH₂OCH₂OCH₃), and(methoxyethoxy)methanyl (—CH₂OCH₂CH₂OCH₃), and the like; amines such as—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, —CH₂NHCH₂CH₃, —CH₂N(CH₂CH₃)(CH₃), and thelike. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heteroalkyl-aryl” refers to a -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl respectively. The“heteroalkyl-aryl” is bonded to the parent molecular structure throughan atom of the heteroalkyl group.

“Heteroalkyl-heteroaryl” refers to a -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl respectively. The“heteroalkyl-heteroaryl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroalkyl-heterocycloalkyl” refers to a-(heteroalkyl)heterocycloalkyl radical where heteroalkyl andheterocycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and heterocycloalkyl respectively. The“heteroalkyl-heterocycloalkyl” is bonded to the parent molecularstructure through an atom of the heteroalkyl group.

“Heteroalkyl-cycloalkyl” refers to a -(heteroalkyl)cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl respectively. The“heteroalkyl-cycloalkyl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroaryl”, or alternatively, “heteroaromatic”, refers to a radical ofa 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic ortricyclic) aromatic ring system (e.g., having 6, 10 or 14 π electronsshared in a cyclic array) having ring carbon atoms and 1 to 6 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5- to 18-membered heteroaryl”). Heteroaryl polycyclic ringsystems can include one or more heteroatoms in one or more rings.Whenever it appears herein, a numerical range such as “5 to 18” refersto each integer in the given range; e.g., “5 to 18 ring atoms” meansthat the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, 7ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to andincluding 18 ring atoms. In one embodiment, bivalent radicals derivedfrom univalent heteroaryl radicals whose names end in “-yl” by removalof one hydrogen atom from the atom with the free valence are named byadding “-idene” to the name of the corresponding univalent radical,e.g., a pyridyl group with two points of attachment is a pyridylidene.

For example, an N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. One or more heteroatom(s) in theheteroaryl radical can be optionally oxidized. One or more nitrogenatoms, if present, can also be optionally quaternized. Heteroaryl alsoincludes ring systems substituted with one or more nitrogen oxide (—O—)substituents, such as pyridinyl N-oxides. The heteroaryl is attached tothe parent molecular structure through any atom of the ring(s).

“Heteroaryl” also includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more aryl groups wherein the pointof attachment to the parent molecular structure is either on the aryl oron the heteroaryl ring, or wherein the heteroaryl ring, as definedabove, is fused with one or more cycloalkyl or heterocyclyl groupswherein the point of attachment to the parent molecular structure is onthe heteroaryl ring. For polycyclic heteroaryl groups wherein one ringdoes not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl andthe like), the point of attachment to the parent molecular structure canbe on either the ring bearing a heteroatom (e.g., 2-indolyl) or the ringthat does not contain a heteroatom (e.g., 5-indolyl). In someembodiments, a heteroaryl group is a 5 to 10 membered aromatic ringsystem having ring carbon atoms and 1 to 4 ring heteroatoms provided inthe aromatic ring system, wherein each heteroatom is independentlyselected from nitrogen, oxygen, phosphorous, and sulfur (“5- to10-membered heteroaryl”). In some embodiments, a heteroaryl group is a5- to 8-membered aromatic ring system having ring carbon atoms and 1 to4 ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, aheteroaryl group is a 5- to 6-membered aromatic ring system having ringcarbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, phosphorous, and sulfur (“5- to 6-membered heteroaryl”). In someembodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatomsindependently selected from nitrogen, oxygen, phosphorous, and sulfur.In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ringheteroatoms independently selected from nitrogen, oxygen, phosphorous,and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur.

Examples of heteroaryls include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.,thienyl).

Unless stated otherwise in the specification, a heteroaryl moiety isoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfonyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heteroaryl-alkyl” refers to a -(heteroaryl)alkyl radical whereheteroaryl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The“heteroaryl-alkyl” is bonded to the parent molecular structure throughany atom of the heteroaryl group.

“Heteroaryl-heterocycloalkyl” refers to an -(heteroaryl)heterocycloalkylradical where heteroaryl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heteroaryl and heterocycloalkylrespectively. The “heteroaryl-heterocycloalkyl” is bonded to the parentmolecular structure through an atom of the heteroaryl group.

“Heteroaryl-cycloalkyl” refers to an -(heteroaryl)cycloalkyl radicalwhere heteroaryl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“heteroaryl-cycloalkyl” is bonded to the parent molecular structurethrough a carbon atom of the heteroaryl group.

“Heterocyclyl”, “heterocycloalkyl” or ‘heterocarbocyclyl” each refer toany 3- to 18-membered non-aromatic radical monocyclic or polycyclicmoiety comprising at least one ring heteroatom selected from nitrogen,oxygen, phosphorous, and sulfur. A heterocyclyl group can be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein thepolycyclic ring systems can be a fused, bridged or spiro ring system.Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or more rings. A heterocyclyl group can be saturated or partiallyunsaturated. Partially unsaturated heterocycloalkyl groups can be termed“heterocycloalkenyl” if the heterocyclyl contains at least one doublebond, or “heterocycloalkynyl” if the heterocyclyl contains at least onetriple bond. Whenever it appears herein, a numerical range such as “5 to18” refers to each integer in the given range; e.g., “5 to 18 ringatoms” means that the heterocyclyl group can consist of 5 ring atoms, 6ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms,etc., up to and including 18 ring atoms. In one embodiment, bivalentradicals derived from univalent heterocyclyl radicals whose names end in“-yl” by removal of one hydrogen atom from the atom with the freevalence are named by adding “-idene” to the name of the correspondingunivalent radical, e.g., a piperidyl group with two points of attachmentis a piperidylidene.

An N-containing heterocyclyl moiety refers to an non-aromatic group inwhich at least one of the ring atoms is a nitrogen atom. Theheteroatom(s) in the heterocyclyl radical can be optionally oxidized.One or more nitrogen atoms, if present, can be optionally quaternized.Heterocyclyl also includes ring systems substituted with one or morenitrogen oxide (—O—) substituents, such as piperidinyl N-oxides. Theheterocyclyl is attached to the parent molecular structure through anyatom of any of the ring(s).

“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment to the parent molecular structure is on the heterocyclylring. In some embodiments, a heterocyclyl group is a 3- to 10-memberednonaromatic ring system having ring carbon atoms and 1 to 4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous, and sulfur (“3- to 10-memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to8-membered nonaromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous, and sulfur (“5- to 8-memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to6-membered nonaromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous, and sulfur (“5- to 6-memberedheterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclylhas 1 to 3 ring heteroatoms independently selected from nitrogen,oxygen, phosphorous, and sulfur. In some embodiments, the 5- to6-membered heterocyclyl has 1 to 2 ring heteroatoms independentlyselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatomselected from nitrogen, oxygen, phosphorous, and sulfur.

Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-memberedheterocyclyls containing 1 heteroatom include, without limitation,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylscontaining 1 heteroatom include, without limitation, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-memberedheterocyclyls containing 2 heteroatoms include, without limitation,dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-memberedheterocyclyls containing 3 heteroatoms include, without limitation,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, dioxanyl, andtriazinanyl. Exemplary 7-membered heterocyclyl groups containing 1heteroatom include, without limitation, azepanyl, oxepanyl andthiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

Unless stated otherwise, heterocyclyl moieties are optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfonyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heterocyclyl-alkyl” refers to a -(heterocyclyl)alkyl radical whereheterocyclyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“heterocyclyl-alkyl” is bonded to the parent molecular structure throughany atom of the heterocyclyl group. The terms “heterocyclyl-alkenyl” and“heterocyclyl-alkynyl” mirror the above description of“heterocyclyl-alkyl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Imino” refers to the “—C(═N—R^(b))—R^(b)” radical where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Phosphate” refers to a —O—P(═O)(OR^(b))₂ radical, where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphonate” refers to a —O—P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphinate” refers to a P(═O)(R^(b))(OR^(b)) radical, where each R^(b)is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable non-limiting examples of suchgroups, unless otherwise specified, include halogen atoms, mesyloxy,p-nitrobenzensulphonyloxy, trifluoromethyloxy, and tosyloxy groups.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, e.g., a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, Fourth Edition, John Wiley & Sons, New York (2006),incorporated herein by reference in its entirety. For example, a hydroxyprotected form is where at least one of the hydroxy groups present in acompound is protected with a hydroxy protecting group. Likewise, aminesand other reactive groups can similarly be protected.

As used herein, the terms “substituted” or “substitution” mean that atleast one hydrogen present on a group atom (e.g., a carbon or nitrogenatom) is replaced with a permissible substituent, e.g., a substituentwhich upon substitution for the hydrogen results in a stable compound,e.g., a compound which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, or other reaction.Unless otherwise indicated, a “substituted” group can have a substituentat one or more substitutable positions of the group, and when more thanone position in any given structure is substituted, the substituent iseither the same or different at each position. Substituents can includeone or more group(s) individually and independently selected from acyl,alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl,aryloxy, amino, amido, azide, carbonate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfonyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), and —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. For example, acycloalkyl substituent can have a halide substituted at one or more ringcarbons, and the like. The protecting groups that can form theprotective derivatives of the above substituents are known to those ofskill in the art and can be found in references such as Greene and Wuts,above.

“Silyl” refers to a —Si(R^(b))₃ radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfanyl”, “sulfide”, and “thio” each refer to the radical —S—R^(b),wherein R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. For instance, an “alkylthio” refers to the“alkyl-S—” radical, and “arylthio” refers to the “aryl-S—” radical, eachof which are bound to the parent molecular group through the S atom. Theterms “sulfide”, “thiol”, “mercapto”, and “mercaptan” can also eachrefer to the group —R^(b)SH.

“Sulfinyl” or “sulfoxide” refers to the —S(O)—R^(b) radical, wherein for“sulfinyl”, R^(b) is H, and for “sulfoxide”, R^(b) is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon), and heteroarylalkyl, unless statedotherwise in the specification, each of which moiety can itself beoptionally substituted as described herein.

“Sulfonyl” or “sulfone” refers to the —S(O₂)—R^(b) radical, whereinR^(b) is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon), and heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfonamidyl” or “sulfonamido” refers to the following radicals:—S(═O)₂—N(R^(b))₂, —N(R^(b))—S(═O)₂—R^(b), —S(═O)₂—N(R^(b))—, or—N(R^(b))—S(═O)₂—, where each R^(b) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon), and heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein. The R^(b) groups in—S(═O)₂—N(R^(b))₂ or —N(R^(b))—S(═O)₂—R^(b) can be taken together withthe nitrogen to which they are attached to form a 4-, 5-, 6-, 7-, or8-membered heterocyclyl ring. In some embodiments, the term designates aC₁-C₄ sulfonamido, wherein each R^(b) in the sulfonamido contains 1carbon, 2 carbons, 3 carbons, or 4 carbons total.

“Sulfoxyl” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR^(b) radical, wherein R^(b) isselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon), and heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Thiocarbonyl” refers to a —(C═S)— radical.

“Urea” refers to a —N(R^(b))—(C═O)—N(R^(b))₂ or—N(R^(b))—(C═O)—N(R^(b))— radical, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon), andheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

Compounds

In one aspect, provided herein are compounds of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

Cy is aryl or heteroaryl substituted by 0 or 1 occurrence of R³ and 0,1, 2, or 3 occurrence(s) of R⁵;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxylor nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4occurrence(s) of R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea, or carbonate;

X is —(CH(R⁹))_(z)—;

Y is —N(R⁹)—C(═O)—, —C(═O)—N(R⁹)—, —C(═O)—N(R⁹)—(CHR⁹)—, —N(R⁹)—S(═O)—,—S(═O)—N(R⁹)—, —S(═O)₂—N(R⁹)—, —N(R⁹)—C(═O)—N(R⁹)—, or —N(R⁹)—S(═O)₂—;

z is an integer of 1, 2, 3, or 4;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl,hydroxyl, or nitro;

each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, orheteroalkyl;

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which issubstituted with one or more R¹⁰, R¹¹, R¹², or R¹³, and

wherein R¹⁰, R¹¹, R¹², and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety;

with the proviso that the compound is not:

In one embodiment, provided herein is a compound of Formula (Ia):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein W_(b) ⁵ is CHR⁸, and Cy, B, X, Y, W_(d), and R⁸ are as definedherein.

In one embodiment, provided herein is a compound of Formula (Ib):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein W_(b) ⁵ is N or CR⁸, and Cy, B, X, Y, W_(d), and R⁸ are asdefined herein.

In some embodiments, W_(b) ⁵ is N. In some embodiments, W_(b) ⁵ is CR⁸.In some embodiments, R⁸ is hydrogen. In some embodiments, W_(b) ⁵ is CH.

In some embodiments, Cy is aryl substituted with 0 or 1 occurrence of R³and 0, 1, 2, or 3 occurrence(s) of R⁵. In some embodiments, Cy is arylsubstituted with 0 occurrence of R³ and 0, 1, 2, or 3 occurrence(s) ofR⁵. In some embodiments, Cy is aryl substituted with 1 occurrence of R³and 0, 1, 2, or 3 occurrence(s) of R⁵. In some embodiments, Cy is arylsubstituted with 0 occurrence of R³ and 0 occurrence of R⁵. In someembodiments, Cy is aryl substituted with 1 occurrence of R³ and 0occurrence of R⁵. In some embodiments, Cy is phenyl substituted with 0or 1 occurrence of R³ and 0, 1, 2, or 3 occurrence(s) of R⁵. In someembodiments, Cy is phenyl substituted with 0 occurrence of R³ and 0occurrence of R⁵. In some embodiments, Cy is phenyl substituted with 1occurrence of R³ and 0 occurrence of R⁵. In some embodiments, Cy isphenyl substituted with 0 occurrence of R³ and 0, 1, 2, or 3occurrence(s) of R⁵. In some embodiments, Cy is phenyl substituted with1 occurrence of R³ and 0, 1, 2, or 3 occurrence(s) of R⁵.

In some embodiments, Cy is heteroaryl substituted with 0 or 1 occurrenceof R³ and 0, 1, 2, or 3 occurrence(s) of R⁵. In some embodiments, Cy is5-membered heteroaryl substituted with 0 or 1 occurrence of R³ and 0, 1,2, or 3 occurrence(s) of R⁵. In some embodiments, Cy is 5-memberedheteroaryl substituted with 0 occurrence of R³ and 0, 1, 2, or 3occurrence(s) of R⁵. In some embodiments, Cy is 5-membered heteroarylsubstituted with 1 occurrence of R³ and 0, 1, 2, or 3 occurrence(s) ofR⁵. In some embodiments, Cy is 6-membered heteroaryl substituted with 0or 1 occurrence of R³ and 0, 1, 2, or 3 occurrence(s) of R⁵. In someembodiments, Cy is 6-membered heteroaryl substituted with 0 occurrenceof R³ and 0, 1, 2, or 3 occurrence(s) of R⁵. In some embodiments, Cy is6-membered heteroaryl substituted with 1 occurrence of R³ and 0, 1, 2,or 3 occurrence(s) of R⁵. In some embodiments, Cy is heteroarylsubstituted with 0 occurrence of R³ and 0, 1, 2, or 3 occurrence(s) ofR⁵. In some embodiments, Cy is heteroaryl substituted with 1 occurrenceof R³ and 0, 1, 2, or 3 occurrence(s) of R⁵. In some embodiments, Cy isheteroaryl substituted with 0 occurrence of R³ and 0 occurrence of R⁵.In some embodiments, Cy is heteroaryl substituted with 1 occurrence ofR³ and 0 occurrence of R⁵. In some embodiments, Cy is heteroarylsubstituted with 0 occurrence of R³ and 1 occurrence of R⁵. In oneembodiment, Cy can be, for example, pyridinyl, pyrimidinyl, pyridazinyl,thiophenyl (i.e., thienyl), furanyl, pyrrolyl, pyrazolyl, oxazolyl,thiazolyl, or isothiazolyl, each of which is optionally substituted.

In some embodiments, Cy is aryl, thiophenyl (i.e., thienyl), orisothiazolyl, each of which is optionally substituted. In someembodiments, Cy is thiophenyl (i.e., thienyl) substituted with 0occurrence of R³ and 1 occurrence of R⁵. In some embodiments, Cy isthiophenyl (i.e., thienyl) substituted with 1 occurrence of R³ and 0occurrence of R⁵. In some embodiments, Cy is isothiazolyl substitutedwith 0 to 1 occurrence of R³ and 0, 1, 2, or 3 occurrence(s) of R⁵. Insome embodiments, Cy is isothiazolyl substituted with 0 occurrence of R³and 1 occurrence of R⁵. In some embodiments, Cy is isothiazolylsubstituted with 1 occurrence of R³ and 0 occurrence of R⁵.

In some embodiments, R³ is halo (e.g., fluoro, chloro). In someembodiments, R³ is hydroxyl. In some embodiments, R³ is cyano. In someembodiments, R³ is alkyl (e.g., C₁-C₄ alkyl, e.g., methyl optionallysubstituted with one or more substituents (e.g., SO₂Me, among others),e.g., methyl or CF₃). In some embodiments, R³ is (C₁-C₄)alkyl (e.g.,CH₃, CH₂CH₃, isopropyl, or CF₃). In some embodiments, R³ is cycloalkyl(e.g., cyclopropyl). In some embodiments, R³ is alkoxyl (e.g., methoxyor OCF₃). In some embodiments, R³ is heteroaryl (e.g., pyridinyl,pyrimidinyl, pyridazinyl, pyridonyl, thienyl, furanyl, pyrrolyl,pyrazolyl, oxazolyl, thiazolyl, or isothiazolyl, e.g., 2-pyridyl,3-pyridyl, 4-pyridyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,1-substituted-3-pyrazolyl, or 1-substituted-4-pyrazolyl, each of whichis optionally substituted substituents, for example, halo, cyano,hydroxyl, alkyl (e.g., haloalkyl) (e.g., methyl or CF₃), heteroalkyl,alkoxyl (e.g., haloalkoxy) (e.g., methoxy, OCF₃, or O-i-Pr), amino,amido, acyl, oxo, sulfinyl, sulfonyl, sulfonamidyl, cycloalkyl, aryl,heteroaryl, or heterocyclyl, among others). In some embodiments, R³ is5- or 6-membered heteroaryl. In some embodiments, R³ is aryl (e.g.,phenyl optionally substituted with one or more substituents, forexample, halo, cyano, hydroxyl, alkyl (e.g., haloalkyl) (e.g., methyl orCF₃), heteroalkyl, alkoxyl (e.g., haloalkoxy) (e.g., methoxy, OCF₃, orO-i-Pr), amino, amido, acyl, oxo, sulfinyl, sulfonyl, sulfonamidyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl, among others). In someembodiment, R³ is substituted or unsubstituted phenyl. In someembodiment, R³ is amino (including, e.g., primary amine, secondaryamine, or tertiary amine radicals, or phenyl or heteroaryl anilineradicals). In some embodiment, R³ is acyl (e.g., formyl oralkylcarbonyl). In some embodiment, R³ is amido. In some embodiment, R³is alkenyl (e.g., —CH₂CH═CH₂). In some embodiments, R³ is alkynyl (e.g.,ethynyl or propynyl, which is optionally substituted, e.g., with amino,amido, sulfonamido, among others).

In some embodiments, R⁵ is halo (e.g., fluoro, chloro). In someembodiments, R⁵ is hydroxyl. In some embodiments, R⁵ is cyano. In someembodiments, R⁵ is alkyl (e.g., C₁-C₄ alkyl, e.g., methyl optionallysubstituted with one or more substituents, e.g., methyl or CF₃). In someembodiments, R⁵ is (C₁-C₄)alkyl (e.g., CH₃, CH₂CH₃, isopropyl, or CF₃).In some embodiments, R⁵ is cycloalkyl (e.g., cyclopropyl). In someembodiments, R⁵ is alkoxyl (e.g., methoxy or OCF₃).

In some embodiments, B is aryl substituted with 0, 1, 2, 3, or 4occurrence(s) of R². In some embodiments, B is phenyl substituted with0, 1, 2, 3, or 4 occurrence(s) of R². In some embodiments, B is phenylsubstituted with 0 occurrence of R². In some embodiments, B is phenylsubstituted with 1 occurrence of R². In some embodiments, B is phenylsubstituted with 2 occurrences of R². In some embodiments, B is phenylsubstituted with 3 occurrences of R². In some embodiments, B is phenylsubstituted with 4 occurrences of R². In some embodiments, B is phenylsubstituted with 0, 1, or 2 occurrence(s) of R².

In some embodiments, B is alkyl (e.g., methyl, ethyl, propyl, orisopropyl) substituted with 0, 1, 2, 3, or 4 occurrence(s) of R². Insome embodiments, B is cycloalkyl (e.g., cyclopropyl, cyclobutyl, orcyclopentyl) substituted with 0, 1, 2, 3, or 4 occurrence(s) of R². Insome embodiments, B is heterocyclyl substituted with 0, 1, 2, 3, or 4occurrence(s) of R². In some embodiments, B is heteroaryl substitutedwith 0, 1, 2, 3, or 4 occurrence(s) of R².

In some embodiments, B is substituted with 0 occurrence of R². In someembodiments, B is substituted with 1 occurrence of R². In someembodiments, B is substituted with 2 occurrences of R². In someembodiments, B is substituted with 3 occurrences of R². In someembodiments, B is substituted with 4 occurrences of R².

In some embodiments, R² is halo (e.g., fluoro or chloro). In someembodiments, R² is cyano. In some embodiments, R² is hydroxyl. In someembodiments, R² is alkyl. In some embodiments, R² is alkoxyl.

In some embodiments, two adjacent occurrences of R² together with theatoms to which they are attached form a ring. In some embodiments, whenB is aryl (e.g., phenyl), heteroaryl, cycloalkyl or heterocyclyl, twoadjacent occurrences of R² together with the atoms to which they areattached form a ring.

In some embodiments, X is —(CH(R⁹))_(z)—. In some embodiments, z is 1.In some embodiments, R⁹ is hydrogen. In some embodiments, R⁹ is C₁₋₁₀alkyl (e.g., methyl or ethyl). In some embodiments, X is —CH(CH₃)—.

In some embodiments, Y is —N(R⁹)—C(═O)—. In some embodiments, R⁹ ishydrogen. In some embodiments, R⁹ is C₁₋₁₀ alkyl (e.g., methyl orethyl). In some embodiments, Y is —N(H)—C(═O)—.

In some embodiments, R⁹ is optionally substituted alkyl (e.g.,—(CH₂)_(n)OH, —(CH₂)_(n)-acid, —(CH₂)_(n)-ester, —(CH₂)_(n)-amine,—(CH₂)_(n)-amide, —(CH₂)_(n)-sulfonamide, or —(CH₂)_(n)-phenyl, amongothers, where n is 0, 1, 2, 3, or 4).

In certain embodiments, —X—Y— is

In some embodiments, —X—Y— is

In some embodiments, —X—Y— is

In certain embodiments, W_(d) is aryl (e.g., a monocyclic aryl or abicyclic aryl). In some embodiments, W_(d) is substituted orunsubstituted phenyl. In some embodiments, W_(d) is bicyclic aryl (e.g.,substituted or unsubstituted naphthyl). In some embodiments, W_(d) is

In certain embodiments, W_(d) is heteroaryl (e.g., monocyclicheteroaryl, e.g., a monocyclic 5- or 6-membered heteroaryl; or bicyclicheteroaryl, e.g., a 5/6-bicyclic heteroaryl or a 6/6-bicyclicheteroaryl). For example, in some embodiments, W_(d) is

wherein

X₁, X₂ and X₃ are each independently C, CR¹³, or N;

X₄, X₅ and X₆ are each independently N, NR¹², CR¹³, S, or O; and

R¹⁰, R¹¹, R¹², and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, W_(d) is heteroaryl (e.g., monocyclicheteroaryl, e.g., a monocyclic 5- or 6-membered heteroaryl; or bicyclicheteroaryl, e.g., a 5/6-bicyclic heteroaryl or a 6/6-bicyclicheteroaryl). For example, in some embodiments, W_(d) is

wherein

X₁, X₂ and X₃ are each independently C, CR¹³, or N;

X₄, X₅ and X₆ are each independently N, NR¹², CR¹³, S, or O; and

R¹⁰, R¹¹, R¹², and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, X₁ is N. In some embodiments, X₁ is CR¹³. Insome embodiments, X₁ is C.

In certain embodiments, X₂ is N. In some embodiments, X₂ is CR¹³. Insome embodiments, X₂ is C.

In certain embodiments, X₃ is N. In some embodiments, X₃ is CR¹³.

In certain embodiments, X₄ is N. In some embodiments, X₄ is CR¹³. Insome embodiments, X₄ is S.

In certain embodiments, X₅ is NR¹². In some embodiments, X₅ is CR¹³. Insome embodiments, X₅ is O. In some embodiments, X₅ is S.

In certain embodiments, X₆ is N. In some embodiments, X₆ is NH. In someembodiments, X₆ is CR¹³. In some embodiments, X₆ is NH. In someembodiments, X₆ is O.

In some embodiments, each R¹⁰ is independently hydrogen, halo (e.g.,fluoro, chloro, or bromo), cyano, hydroxyl, alkyl (e.g., methyl or CF₃),alkoxyl, amino (e.g., cycloalkylamino (e.g., cyclopropylamino),alkylamino (e.g., methylamino or dimethylamino), or NH₂), aryl (e.g.,substituted or unsubstituted phenyl), heteroaryl (e.g., a 5- or6-membered heteroaryl, e.g., pyrazolyl, pyridinyl, among others),heterocyclyl (e.g., N-morpholinyl), or amido. In some embodiments, eachR¹⁰ is independently hydrogen, alkyl (e.g., methyl), amino (e.g.,cyclopropylamino, methylamino or NH₂), heterocyclyl (e.g.,N-morpholinyl), heteroaryl (e.g., 4-pyrazolyl), amido or halo (e.g.,chloro). In one embodiment, R¹⁰ is NH₂. In one embodiment, R¹⁰ is H.

In certain embodiments, each R¹¹ is independently hydrogen, halo (e.g.,fluoro, chloro, or bromo), cyano, hydroxyl, alkyl (e.g., methyl or CF₃),alkoxyl, amino (e.g., cycloalkylamino (e.g., cyclopropylamino),alkylamino (e.g., methylamino or dimethylamino), or NH₂), aryl (e.g.,substituted or unsubstituted phenyl), heteroaryl (e.g., a 5- or6-membered heteroaryl, e.g., pyrazolyl, pyridinyl, among others),heterocyclyl (e.g., N-morpholinyl), or amido. In some embodiments, eachR¹¹ is independently hydrogen, amino, halo (e.g., bromo), aryl (e.g.,phenyl) or alkyl (e.g., methyl). In one embodiment, R¹¹ is H.

In certain embodiments, each R¹² is independently hydrogen, halo (e.g.,fluoro, chloro, or bromo), cyano, hydroxyl, alkyl (e.g., methyl or CF₃),alkoxyl, amino (e.g., cycloalkylamino (e.g., cyclopropylamino),alkylamino (e.g., methylamino or dimethylamino), or NH₂), aryl (e.g.,substituted or unsubstituted phenyl), heteroaryl (e.g., a 5- or6-membered heteroaryl, e.g., pyrazolyl, pyridinyl, among others),heterocyclyl (e.g., N-morpholinyl), or amido. In some embodiments, eachR¹² is independently hydrogen, amino, or alkyl (e.g., methyl). In oneembodiment, R¹² is H.

In certain embodiments, each R¹³ is independently hydrogen, halo (e.g.,fluoro, chloro, or bromo), cyano, hydroxyl, alkyl (e.g., methyl or CF₃),alkoxyl, amino (e.g., cycloalkylamino (e.g., cyclopropylamino),alkylamino (e.g., methylamino or dimethylamino), or NH₂), aryl (e.g.,substituted or unsubstituted phenyl), heteroaryl (e.g., a 5- or6-membered heteroaryl, e.g., pyrazolyl, pyridinyl, among others),heterocyclyl (e.g., N-morpholinyl), or amido. In some embodiments, eachR¹³ is independently hydrogen, amino (e.g., NH₂), amido (e.g.,NH—C(═O)Me), or alkyl (e.g., methyl). In one embodiment, R¹³ is H.

In some embodiments, W_(d) is:

wherein one of X₁ and X₂ is C and the other is N; R¹⁰ is H or NH₂; andR¹¹, R¹², and R¹³ are as defined herein. In specific embodiments, R¹⁰ isNH₂. In specific embodiments, two of R¹¹, R¹², and R¹³ are H, and one ofR¹¹, R¹², and R¹³ is alkyl (e.g., methyl or CF₃), halo, cyano, aryl(e.g., phenyl), or heteroaryl (e.g., a 5- or 6-membered heteroaryl, suchas, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, amongothers); and in some embodiments, the aryl and heteroaryl is optionallysubstituted with one or more substituents, such as, for example, halo(e.g., F or Cl), cyano, hydroxyl, alkyl (e.g., methyl or CF₃), alkoxyl(e.g., methoxy, OCF₃, ethoxy, or isopropyloxy), sulfonyl (e.g.,S(O)₂Me), sulfonamidyl (e.g., S(O)₂NH₂, S(O)₂NHMe, S(O)₂N(Me)₂,S(O)₂NH-i-Pr, S(O)₂NH-t-Bu, S(O)₂NH-c-Pr, S(O)₂NHPh,S(O)₂—N-pyrrolidinyl, S(O)₂—N-morpholinyl, S(O)₂—N-piperazinyl,S(O)₂-4-methyl-N-piperazinyl, NHS(O)₂Me, NHS(O)₂Et, NHS(O)₂-c-Pr), orsulfonylurea (e.g., NHS(O)₂N(Me)₂).

In some embodiments, W_(d) is:

wherein X₃ is N or CR¹³; R¹⁰ is H or NH₂; and R¹¹, R¹², and R¹³ are asdefined herein. In specific embodiments, R¹⁰ is NH₂. In specificembodiments, X₃ is N. In specific embodiments, one of R¹¹ and R¹² is H,and the other is alkyl (e.g., methyl or CF₃), halo, cyano, aryl (e.g.,phenyl), or heteroaryl (e.g., a 5- or 6-membered heteroaryl, such as,pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, among others);and in some embodiments, the aryl and heteroaryl is optionallysubstituted with one or more substituents, such as, for example, halo(e.g., F or Cl), cyano, hydroxyl, alkyl (e.g., methyl or CF₃), alkoxyl(e.g., methoxy, OCF₃, ethoxy, or isopropyloxy), sulfonyl (e.g.,S(O)₂Me), sulfonamidyl (e.g., S(O)₂NH₂, S(O)₂NHMe, S(O)₂N(Me)₂,S(O)₂NH-i-Pr, S(O)₂NH-t-Bu, S(O)₂NH-c-Pr, S(O)₂NHPh,S(O)₂N-pyrrolidinyl, S(O)₂N-morpholinyl, S(O)₂N-piperazinyl,S(O)₂-4-methyl-N-piperazinyl, NHS(O)₂Me, NHS(O)₂-c-Pr), or sulfonylurea(e.g., NHS(O)₂N(Me)₂).

In some embodiments, W_(d) is:

wherein one of X₁ and X₂ is N and the other is CR¹³; R¹⁰ is H or NH₂;and R¹¹, R¹², and R¹³ are as defined herein. In specific embodiments, X₁is N and X₂ is CR¹³. In specific embodiments, X₁ is N and X₂ is CH. Inspecific embodiments, R¹⁰ is NH₂. In specific embodiments, R¹¹, R¹² andR¹³ are H. In specific embodiments, at least one of R¹¹, R¹² and R¹³ isnot H. In specific embodiments, one occurrence of R¹¹, R¹² and R¹³ isnot H and the other occurrences of R¹¹, R¹² and R¹³ are H, and the oneoccurrence of R¹¹, R¹² and R¹³ (which is not hydrogen) is alkyl (e.g.,methyl or CF₃), halo, cyano, aryl (e.g., phenyl), or heteroaryl (e.g., a5- or 6-membered heteroaryl, such as, pyridinyl, pyrimidinyl, pyrazolyl,thiazolyl, imidazolyl, among others); and in some embodiments, the aryland heteroaryl is optionally substituted with one or more substituents,such as, for example, halo (e.g., F or Cl), cyano, hydroxyl, alkyl(e.g., methyl or CF₃), alkoxyl (e.g., methoxy, OCF₃, ethoxy, orisopropyloxy), sulfonyl (e.g., S(O)₂Me), sulfonamidyl (e.g., S(O)₂NH₂,S(O)₂NHMe, S(O)₂N(Me)₂, S(O)₂NH-i-Pr, S(O)₂NH-t-Bu, S(O)₂NH-c-Pr,S(O)₂NHPh, S(O)₂N-pyrrolidinyl, S(O)₂N-morpholinyl, S(O)₂N-piperazinyl,S(O)₂-4-methyl-N-piperazinyl, NHS(O)₂Me, NHS(O)₂-c-Pr), or sulfonylurea(e.g., NHS(O)₂N(Me)₂).

In exemplary embodiments, W_(d) is one of the following moieties:

wherein R¹¹ and R¹² are as defined herein.

In some embodiments, B is unsubstituted or substituted alkyl, including,but not limited to, —(CH₂)₂—NR^(a)R^(a), wherein each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; or NR^(a)R^(a) are combined together to form a cyclicmoiety, which includes, but is not limited to, piperidinyl, piperazinyl,and morpholinyl, each of which is optionally substituted. In someembodiments, B is unsubstituted or substituted amino. In someembodiments, B is unsubstituted or substituted hetero alkyl.

In some embodiments, B is selected from unsubstituted or substitutedaryl, including, but not limited to, unsubstituted or substitutedphenyl; unsubstituted or substituted heteroaryl, including, but notlimited to, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl,pyrimidin-2-yl, pyrimidin-5-yl, and pyrazin-2-yl; unsubstituted orsubstituted monocyclic heteroaryl; unsubstituted or substituted bicyclicheteroaryl; unsubstituted or substituted heteroaryl having twoheteroatoms as ring atoms; unsubstituted or substituted heteroarylhaving a nitrogen ring atom; unsubstituted or substituted heteroarylhaving two nitrogen ring atoms; unsubstituted or substituted heteroarylhaving a nitrogen and a sulfur as ring atoms; unsubstituted orsubstituted heterocyclyl including, but not limited to, morpholinyl,tetrahydropyranyl, piperazinyl, and piperidinyl; and unsubstituted orsubstituted cycloalkyl, including, but not limited to, cyclopentyl andcyclohexyl.

In some embodiments, B is aryl, heteroaryl, alkyl, cycloalkyl, orheterocyclyl, each of which is substituted with 0, 1, 2, or 3occurrence(s) of R². In some embodiments, B is phenyl substituted with0, 1, 2, or 3 occurrence(s) of R². In some embodiments, B isunsubstituted phenyl. In some embodiments, B is phenyl substituted with1 or 2 occurrence(s) of R². In some embodiments, R² is halo or alkyl. Insome embodiments, B is methyl, isopropyl, or cyclopropyl. In someembodiments, B is cyclohexyl or optionally substituted alkyl.

In some embodiments, B is one of the following moieties: —CH₃, —CH₂CH₃,—CH(CH₃)₂,

In some embodiments, B is unsubstituted or substituted with one or moreR² substituents. In some embodiments, R² is alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl alkoxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, or sulfonamido, can itself be substituted.

In some embodiments, R² is unsubstituted or substituted alkyl,unsubstituted or substituted heteroalkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted cycloalkyl, or unsubstituted or substituted heterocyclyl. Insome embodiments, R² is unsubstituted or substituted aryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroaryl, orunsubstituted or substituted heteroarylalkyl. In some embodiments, R² isunsubstituted or substituted alkoxy, unsubstituted or substituted amido,or unsubstituted or substituted amino. In some embodiments, R² isunsubstituted or substituted acyl, unsubstituted or substituted acyloxy,unsubstituted or substituted alkoxycarbonyl, or unsubstituted orsubstituted sulfonamido. In some embodiments, R² is halo, selected from—I, —F, —Cl, and —Br. In some embodiments, R² is selected from cyano,hydroxyl, nitro, and a carbonate. In some embodiments, R² isunsubstituted or substituted phosphate. In some embodiments, R² isunsubstituted or substituted urea. In some embodiments, when R² isalkyl, R² is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, pentyl, hexyl or heptyl, each of which is optionallysubstituted.

In some embodiments, when R² is alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, orhydroxyl, it is substituted by phosphate, substituted by urea, orsubstituted by carbonate.

In some embodiments, when R² is alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido, itis substituted by one or more of alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, or nitro,each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments, there is no occurrence of R². In other embodiments,there is one occurrence of R². In still other embodiments, there are twooccurrences of R². In yet other embodiments, there are three occurrencesof R². In yet other embodiments, there are four occurrences of R². Forexample, in some embodiments, B is aryl or heteroaryl, and there is nooccurrence of R². In other instances, B is aryl or heteroaryl, and thereis one occurrence of R², and in some embodiment, R² is alkyl or halo.

In some embodiments, R³ is alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, aryl, heteroaryl, hydroxyl, or nitro. In some embodiments, R³ isalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl,hydroxyl, or nitro; each of which is substituted with 0, 1, 2, 3, or 4occurrence(s) of R².

In some embodiments, R³ is hydrogen, halo, cyano, hydroxy, alkyl,alkenyl, alkynyl, alkoxy, amino, acyl, heteroaryl, aryl, heterocyclyl,or cycloalkyl. In some embodiments, R³ is hydrogen, halo, cyano,hydroxy, alkyl, alkenyl, alkynyl, alkoxy, amino, acyl, heteroaryl, aryl,heterocyclyl, or cycloalkyl; each of which is substituted with 0, 1, 2,3, or 4 occurrence(s) of R².

In some embodiments, R³ is hydrogen, halo, cyano, hydroxy, alkyl,alkoxy, heteroaryl, aryl, heterocyclyl, or cycloalkyl. In someembodiments, R³ is hydrogen, halo, cyano, hydroxy, alkyl, alkoxy,heteroaryl, aryl, heterocyclyl, or cycloalkyl; each of which issubstituted with 0, 1, 2, 3, or 4 occurrence(s) of R².

In some embodiments, R³ is halo, alkyl, alkoxy, heteroaryl, orcycloalkyl. For example, in some embodiments, R³ is H, CH₃, CH₂CH₃, CF₃,Cl, or F. In other embodiments, R³ is CH₃, CF₃, or Cl.

In some embodiments, R³ is heteroaryl, aryl, alkyl, haloalkyl, OH, Cl,or F. In some embodiments, R³ is heteroaryl, substituted orunsubstituted phenyl, CH₃, CF₃, OH, or Cl. In some embodiments, R³ isCH₃, OCH₃, CF₃, or halo. In some embodiments, R³ is OCF₃, CN,cyclopropyl, CH₂OH, amino, formyl, heterocyclyl, alkenyl, or alkynyl.

In some embodiments, each R³ and R⁸ is independently selected from CH₃,OCH₃, CF₃, and halo.

In some embodiments, R⁸ is H, CH₃, OCH₃, CF₃, CN, or halo. In someembodiments, R⁸ is H, CH₃, OCH₃, CF₃, or halo. In some embodiments, R⁸is hydrogen. In some embodiments, R⁸ is hydrogen, alkyl, cyano, or halo.In some embodiments, R⁸ is hydrogen, methyl, cyano, or bromo. In someembodiments, R⁹ is alkyl (e.g., methyl or ethyl). In some embodiments,R⁹ is methyl. In some embodiments, R⁹ is hydrogen.

In some embodiments, R³ is unsubstituted or substituted alkyl,unsubstituted or substituted alkenyl, or unsubstituted or substitutedalkynyl. In some embodiments, R³ is unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedcycloalkyl, or unsubstituted or substituted heterocyclyl. In someembodiments, R³ is unsubstituted or substituted alkoxy, unsubstituted orsubstituted amido, unsubstituted or substituted amino. In someembodiments, R³ is unsubstituted or substituted acyl, unsubstituted orsubstituted acyloxy, unsubstituted or substituted alkoxycarbonyl, orunsubstituted or substituted sulfonamido. In some embodiments, R³ ishalo, selected from —I, —F, —Cl, and —Br. In some embodiments, R³ ishalo, alkyl, alkoxy, heteroaryl, or cycloalkyl. For example, in someembodiments, R³ is —CH₃, —CH₂CH₃, —CF₃, —Cl, or —F. In some instances,R³ is —CH₃, —CF₃, or —Cl.

In some embodiments, R³ is selected from cyano, hydroxyl, and nitro. Insome embodiments, when R³ is alkyl, R³ is methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl or heptyl. Insome embodiments, R³ is —CF₃, —CH₂F, or —CHF₂.

In some embodiments, when R³ is alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclyl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, or sulfonamido, it is substituted with one ormore of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, or nitro, each of which alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, orsulfonamido can itself be substituted.

In some embodiments, R³ is a 5-membered heteroaryl group. Such groupsinclude, for example, pyrrole, furan, thiophene, triazole, oxazole,pyrazole, and isoxazole, each of which is optionally substituted. Inother embodiments, R³ is a 5-membered nonaromatic heterocyclyl,including, but not limited to, oxazoline and oxazolidinone, each ofwhich is optionally substituted. In still other embodiments, R³ is a6-membered heteroaryl group, including, but not limited to, pyridine,pyrazine, pyrimidine and pyridazine, each of which is optionallysubstituted. Alternatively, R³ is a 6-membered nonaromatic heterocyclyl,including moieties such as morpholinyl or piperidinyl, each of which isoptionally substituted. In other embodiments, R³ is a fused 5/6-bicyclicheteroaryl, including, for example, benzothiazole, benzoxazole,benzisoxazole, indazole, benzimidazole, benzothiophene, indole,isoindole, purine, or pyrazolopyrimidine, each of which is optionallysubstituted. In yet other embodiments, R³ is a fused 5/6-bicyclicnonaromatic heterocyclyl.

In some embodiments, R³ is a C₁-C₆ alkyl group substituted with a5-membered heteroaryl, a 5-membered heterocyclyl, a 6-memberedheteroaryl, a 6-membered heterocyclyl, a fused 5/6-bicyclic heteroaryl,or a fused 5/6-bicyclic heterocyclyl. Alternatively, R³ is amino,sulfinyl, sulfonyl, sulfoxide, sulfone, or alkoxy, wherein the N, S, orO heteroatom is connected, either directly via a covalent bond orthrough a C₁-C₆ alkyl group, to a 5-membered heteroaryl, a 5-memberedheterocyclyl, a 6-membered heteroaryl, a 6-membered heterocyclyl, afused 5/6-bicyclic heteroaryl, or a fused 5/6-bicyclic heterocyclyl.

In other embodiments, R³ is a C₁-C₆ alkyl group substituted with a fusedpolycyclic group, wherein the polycyclic group has greater than tworings and is cycloalkyl or heterocyclyl; a C₁-C₆ alkyl group substitutedwith a bridged cycloalkyl or a bridged heterocyclyl group; a C₁-C₆ alkylgroup substituted with a spirocyclic cycloalkyl or a spirocyclicheterocyclyl group; or a branched C₄-C₁₂ alkyl group, wherein saidbranched alkyl group contains at least one terminal t-butyl group.

Each of the embodiments named above for R³ is unsubstituted oroptionally additionally substituted with an alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, or nitro group.

In certain embodiments, R³ is a substituted or unsubstitutedheterocyclyl or heteroaryl group selected from pyridine, pyrimidine,pyridone, pyrazole, piperazine, and pyrrolidine, wherein the substituentcan be a C₁-C₆ alkyl, a C₁-C₆ alkoxyl, a sulfonyl, a sulfonamide, or ahalogen.

In some embodiments, a compound is provided wherein R³ is selected froma 5-membered heteroaryl, such as pyrrole, furan, or thiophene; a5-membered heterocyclyl, such as pyrrolidine, tetrahydrofuran, ortetrahydro-thiophene; a 6-membered heteroaryl, such as pyridine,pyrazine, pyrimidine, or pyridazine; a 6-membered heterocyclyl, such aspiperidine, tetrahydropyran, or thiane; and a fused 5/6-bicyclicheteroaryl, such as indole, isoindole, benzofuran, isobenzofuran,benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, orpurine; each of which is substituted or unsubstituted. In certainembodiments, R³ is a substituted or unsubstituted group selected frompyridine, pyrazole, piperazine, and pyrrolidine. By way of non-limitingexample, the R³ group can be substituted with a C₁-C₆ alkyl group or ahalogen. For example, the R³ group can be substituted with a methylgroup.

In some embodiments, a compound is provided wherein R³ is selected from:

wherein X is NR, S or O; R is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, sulfonyl,sulfonamido, halo, or haloalkyl. In certain embodiments, R is methyl.

In other embodiments, a compound is provided wherein R³ is selectedfrom:

In other embodiments, a compound is provided wherein R³ is Cl, OH, OCH₃,CH₃, or CF₃. In one embodiment, a compound is provided wherein R³ is Cl,CH₃, or CF₃.

In some embodiments, each R⁵ is independently unsubstituted orsubstituted alkyl, including, but not limited to, unsubstituted orsubstituted C₁-C₄ alkyl. In some embodiments, each R⁵ is independentlyunsubstituted or substituted alkenyl, including, but not limited to,unsubstituted or substituted C₂-C₅ alkenyl. In some embodiments, each R⁵is independently unsubstituted or substituted alkynyl, including, butnot limited to, unsubstituted or substituted C₂-C₅ alkynyl. In someembodiments, each R⁵ is independently unsubstituted or substitutedcycloalkyl, including, but not limited to, unsubstituted or substitutedC₃-C₅ cycloalkyl. In some embodiments, each R⁵ is independentlyunsubstituted or substituted heterocyclyl. In some embodiments, each R⁵is independently unsubstituted or substituted heteroalkyl, including,but not limited to, unsubstituted or substituted C₁-C₄ heteroalkyl. Insome embodiments, each R⁵ is independently unsubstituted or substitutedalkoxy, including, but not limited to, unsubstituted or substitutedC₁-C₄ alkoxy. In some embodiments, each R⁵ is independentlyunsubstituted or substituted amido, including, but not limited to,unsubstituted or substituted C₁-C₄ amido. In some embodiments, each R⁵is independently unsubstituted or substituted amino. In someembodiments, each R⁵ is independently unsubstituted or substituted acyl,unsubstituted or substituted acyloxy (e.g., unsubstituted or substitutedC₁-C₄ acyloxy), unsubstituted or substituted alkoxycarbonyl,unsubstituted or substituted sulfonamido (e.g., unsubstituted orsubstituted C₁-C₄ sulfonamido). In some embodiments, each R⁵ isindependently halo, selected from —I, —F, —Cl, and —Br. In someembodiments, each R⁵ is independently selected from cyano, hydroxyl, andnitro. In some embodiments, each R⁵ is independently —CH₃, —CH₂CH₃,n-propyl, isopropyl, —OCH₃, —OCH₂CH₃, or —CF₃.

In some embodiments, when R⁵ is alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl, orsulfonamido, R⁵ is independently optionally substituted with one or moreof alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, or nitro, each of which alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, orsulfonamido can itself be substituted.

In some embodiments, no R⁵ moieties are present.

In some embodiments, X is absent. In some embodiments, X is—(CH(R⁹))_(z)—, and z is an integer of 1, 2, 3 or 4. In someembodiments, X is —CH(R⁹)—. In some embodiments, X is —(CH(R⁹))₂—. Insome embodiments, X is —(CH(R⁹))₃—. In some embodiments, X is—(CH(R⁹))₄—.

In some embodiments, R⁹ is unsubstituted or substituted alkyl,including, but not limited to, unsubstituted or substituted C₁-C₁₀alkyl. In some embodiments, R⁹ is unsubstituted or substitutedcycloalkyl, including, but not limited to, unsubstituted or substitutedC₃-C₇ cycloalkyl. In some embodiments, R⁹ is ethyl, methyl, or hydrogen.In some embodiments, R⁹ is unsubstituted or substituted heterocyclyl,including, but not limited to, unsubstituted or substituted C₂-C₁₀heterocyclyl. In some embodiments, R⁹ is unsubstituted or substitutedheteroalkyl including, but not limited to, unsubstituted or substitutedC₂-C₁₀ heteroalkyl.

Also provided herein is a compound of Formula (I), wherein R⁹ ishydrogen, and X is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or—CH(CH₂CH₃)—. In other embodiments, X is —(CH(R⁹))_(z)— wherein R⁹ isnot hydrogen, and z is an integer of 1. When X is —CH(R⁹)— wherein R⁹ isnot hydrogen, then the compound can adopt either an (S)- or(R)-stereochemical configuration with respect to the CH carbon. In someembodiments, the compound is a racemic mixture of (S)- and (R)-isomerswith respect to CH carbon. In other embodiments, provided herein is amixture of compounds of Formula (I) wherein individual compounds of themixture exist predominately in an (S)- or (R)-isomeric configuration.For example, in some embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about96%, about 97%, about 98%, about 99%, about 99.5%, or more at the Xcarbon. In some embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 10%, greater than about20%, greater than about 30%, greater than about 40%, greater than about50%, greater than about 55%, greater than about 60%, greater than about65%, greater than about 70%, greater than about 75%, greater than about80%, greater than about 85%, greater than about 90%, greater than about95%, greater than about 96%, greater than about 97%, greater than about98%, greater than about 99%, or greater than about 99.5%, or more at theX carbon. In other embodiments, the compound mixture has an(S)-enantiomeric excess of about 10% to about 99.5%, about 20% to about99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% toabout 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%,about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% toabout 99.5%, about 98% to about 99.5%, about 99% to about 99.5%, or moreat the X carbon.

In other embodiments, the compound mixture has an (R)-enantiomericexcess of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5%, or more at the X carbon. In someembodiments, the compound mixture has an (R)-enantiomeric excess ofgreater than about 10%, greater than about 20%, greater than about 30%,greater than about 40%, greater than about 50%, greater than about 55%,greater than about 60%, greater than about 65%, greater than about 70%,greater than about 75%, greater than about 80%, greater than about 85%,greater than about 90%, greater than about 95%, greater than about 96%,greater than about 97%, greater than about 98%, greater than about 99%,or greater than about 99.5%, or more at the X carbon. In otherembodiments, the compound mixture has an (R)-enantiomeric excess ofabout 10% to about 99.5%, about 20% to about 99.5%, about 30% to about99.5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% toabout 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%,about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% toabout 99.5%, about 99% to about 99.5%, or more at the X carbon.

In some embodiments of a compound of Formula (I), X is —CH(R⁹)— whereinR⁹ is methyl or ethyl, and the compound is an (S)-isomer.

In some embodiments of a compound of Formula (I), Y is —N(R⁹)(C═O)wherein R⁹ is H or substituted or unsubstituted alkyl. For example, insome embodiments, Y is —N(H)(C═O)—.

In some embodiments, W_(d) is aryl, monocyclic heteroaryl, a5/6-bicyclic heteroaryl, or a 6/6-bicyclic heteroaryl.

In some embodiments, W_(d) is

wherein

one of X₁ and X₂ is N and one of X₁ and X₂ is C or CR¹³;

X₃ is CR¹³ or N; and

R¹⁰, R¹¹, R¹², and R¹³ are as defined herein elsewhere.

In specific embodiments, W_(d) is

In specific embodiments, W_(d) is

wherein R¹⁰, R¹¹, and R¹² are as defined herein.

In specific embodiments, W_(d) is

In some embodiments, R¹⁰ is NH₂.

In some embodiments, at least one of R¹⁰, R¹¹, R¹² and R¹³ is hydrogen,cyano, halo, unsubstituted or substituted alkyl, unsubstituted orsubstituted alkynyl, or unsubstituted or substituted alkenyl. In someembodiments, at least one of R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted orsubstituted aryl. In some embodiments, at least one of R¹⁰, R¹¹, R¹² andR¹³ is unsubstituted or substituted heteroaryl, which includes, but isnot limited to, heteroaryl having a 5-membered ring, heteroaryl having a6-membered ring, heteroaryl with at least one nitrogen ring atom,heteroaryl with two nitrogen ring atoms, monocyclic heteroaryl, andbicyclic heteroaryl. In some embodiments, at least one of R¹⁰, R¹¹, R¹²and R¹³ is unsubstituted or substituted heterocyclyl, which includes,but is not limited to, heterocyclyl with one nitrogen ring atom,heterocyclyl with one oxygen ring atom, heterocyclyl with one sulfurring atom, 5 membered heterocyclyl, 6-membered heterocyclyl, saturatedheterocyclyl, unsaturated heterocyclyl, heterocyclyl having anunsaturated moiety connected to the heterocyclyl ring, heterocyclylsubstituted by oxo, and heterocyclyl substituted by two oxo. In someembodiments, at least one of R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted orsubstituted cycloalkyl, including, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloalkyl, each of which can beunsubstituted or substituted by one oxo; or cycloalkyl having anunsaturated moiety connected to the cycloalkyl ring. In someembodiments, at least one of R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted orsubstituted amido, unsubstituted or substituted acyloxy, unsubstitutedor substituted alkoxycarbonyl, unsubstituted or substituted acyl, orunsubstituted or substituted sulfonamido.

In some embodiments, when at least one of R¹⁰, R¹¹, R¹² and R¹³ isalkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkoxycarbonyl, amido, acyloxy, acyl, or sulfonamido, it is substitutedwith one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, or nitro, each ofwhich alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,or sulfonamido can itself be substituted.

In some embodiments of a compound of Formula (I), W_(d) is:

wherein X₃ is CR¹³ or N; and R¹⁰, R¹¹, R¹², and R¹³ are as definedherein elsewhere.

In some embodiments, W_(d) is

wherein R¹⁰ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate,or NR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety; and X₃ is as defined herein. For example, in someembodiments, R¹⁰ is amino or NR′R″ wherein R′ and R″ are taken togetherwith nitrogen to form a cyclic moiety.

In some embodiments, W_(d) is

wherein R¹⁰, R¹¹, and R¹² are as defined herein.

In some embodiments, W_(d) is

wherein R¹⁰, R¹¹, and R¹² are as defined herein. For example, in someembodiments, W_(d) is

In other embodiments of a compound of Formula (I), W_(d) is:

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is C; and R¹⁰, R¹¹,R¹², and R¹³ are as defined herein elsewhere. In some embodiments, W_(d)is

For example, in some embodiments, W_(d) is

In other embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments of a compound of Formula (I), W_(d) is

In some embodiments of a compound of Formula (I), W_(d) is

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is CR¹³; and R¹⁰,R¹¹, R¹², and R¹³ are as defined herein elsewhere. In some embodiments,W_(d) is

In some embodiments, W_(d) is

In some embodiments of a compound of Formula (I), W_(d) is not

In some embodiments of a compound of Formula (I), the compound is not:

In some embodiments, the compound of Formula (I) has a structure ofFormula (II):

In some embodiments, the compound of Formula (II) can have a structureof Formula (IIa) or Formula (IIb):

In some embodiments, the compound of Formula (I) has a structure ofFormula (IIc):

In some embodiments, the compound of Formula (IIa) or (IIb) has astructure of Formula (IIIa) or Formula (IIIb):

In some embodiments, the compound of Formula (IIc) has a structure ofFormula (IIIc):

In some embodiments, the compound of Formula (IIIc) has a structure ofFormula (IIId):

In some embodiments, R⁸ is hydrogen.

In some embodiments, R⁹ is methyl.

In some embodiments of a compound of Formula (IIa), (IIb), (IIc),(IIIa), (IIIb), (IIIc), or (IIId), W_(d) is:

wherein X₃ is CR¹³ or N; and R¹⁰, R¹¹, R¹², and R¹³ are as definedherein elsewhere.

In specific embodiments, W_(d) is

wherein X₃ is as defined herein elsewhere, and R¹⁰ is hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety. For example,R¹⁰ is amino or NR′R″ wherein R′ and R″ are taken together with nitrogento form a cyclic moiety.

In specific embodiments, W_(d) is

wherein R¹⁰, R¹¹, and R¹² are as defined herein. For example, in someembodiments, W_(d) is

In other embodiments of a compound of Formula (IIa), (IIb), (IIc),(IIIa), (IIIb), (IIIc), or (IIId), W_(d) is:

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is C; and R¹⁰, R¹¹,R¹², and R¹³ are as defined herein elsewhere.

In some embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In other embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments of a compound of Formula (IIa), (IIb), (IIc),(IIIa), (IIIb), (IIIc), or (IIId), W_(d) is

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is CR¹³; and R¹⁰,R¹¹, R¹², and R¹³ are as defined herein elsewhere.

In some embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments of a compound of Formula (IIa), (IIb), (IIc),(IIIa), (IIIb), (IIIc), or (IIId), B is aryl substituted with 0, 1, 2,or 3 occurrence(s) of R². For example, in some embodiments, B is phenylsubstituted with 0, 1, 2, or 3 occurrence(s) of R². In some embodimentsof a compound of Formula (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), or(IIId), B is unsubstituted phenyl. In other embodiments of a compound ofFormula (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), or (IIId), B isphenyl substituted with 1 occurrence of R². In some embodiments, R² ishalo or alkyl. In other embodiments of a compound of Formula (IIa),(IIb), (IIc), (IIIa), (IIIb), (IIIc), or (IIId), B is cycloalkyl orheterocyclyl.

In still other embodiments, the compound of Formula (I) is a compoundwhich has the structure:

In some embodiments, the compound of Formula (I) has a structure ofFormula (IVa) or Formula (IVb):

In some embodiments, the compound of Formula (IVa) or Formula (IVb) hasa structure of Formula (Va) or Formula (Vb):

In some embodiments of a compound of Formula (IVa), (IVb), (Va), or(Vb), W_(b) ⁵ is CR⁸. For example, in some embodiments, W_(b) ⁵ is CH.

In some embodiments of a compound of Formula (IVa) or (Va), R⁵ is H. Insome embodiments of a compounds of Formula (IVa) or (Va), R⁵ is selectedfrom hydrogen, alkyl, cycloalkyl, halo, aryl, and heteroaryl. In someembodiments, R⁵ is selected from alkyl, cycloalkyl, halo, aryl, andheteroaryl. For example, in some embodiments, R⁵ is selected frommethyl, chloro, and pyrazolo.

In some embodiments of a compound of Formula (IVa), (IVb), (Va), or(Vb), W_(d) is:

wherein X₃ is CR¹³ or N; and R¹⁰, R¹¹, R¹², and R¹³ are as definedherein elsewhere.

In specific embodiments, W_(d) is

wherein X₃ is as defined herein elsewhere, and R¹⁰ is hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″are taken together with nitrogen to form a cyclic moiety. For example,in some embodiments, R¹⁰ is amino or NR′R″, wherein R′ and R″ are takentogether with nitrogen to form a cyclic moiety.

In specific embodiments, W_(d) is

wherein R¹⁰, R¹¹, and R¹² are as defined herein. For example, in someembodiments, W_(d) is

In other embodiments of a compound of Formula (IVa), (IVb), (Va), or(Vb), W_(d) is:

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is C; and R¹⁰, R¹¹,R¹², and R¹³ are as defined herein elsewhere.

In some embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In other embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments of a compound of Formula (IVa), (IVb), (Va), or(Vb), W_(d) is

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is CR¹³; and R¹⁰,R¹¹, R¹², and R¹³ are as defined herein elsewhere.

In some embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments of a compound of Formula (IVa), (IVb), (Va), or(Vb), B is aryl substituted with 0, 1, 2, or 3 occurrence(s) of R². Forexample, in some embodiments, B is phenyl substituted with 0, 1, 2, or 3occurrence(s) of R². In some embodiments of a compound of Formula (IVa),(IVb), (Va), or (Vb), B is unsubstituted phenyl. In other embodiments ofa compound of Formula (IVa), (IVb), (Va), or (Vb), B is phenylsubstituted with 1 occurrence of R². In some embodiments, R² is halo oralkyl. In other embodiments of a compound of Formula (IVa), (IVb), (Va),or (Vb), B is cycloalkyl or heterocyclyl.

In other embodiments, the compound of Formula (I) has a structure ofFormula (VIa) or Formula (VIb):

In other embodiments, the compound of Formula (VIa) or (VIb) has astructure of Formula (VIIa) or Formula (VIIb):

In some embodiments, the compound of Formula (VIIa) or (VIIb) has astructure of Formula (VIIIa) or Formula (VIIIb):

In some embodiments, the compound of Formula (VIIIa) or (VIIIb) has astructure of Formula (IXa) or Formula (IXb):

In other embodiments, the compound of Formula (I) has a structure ofFormula (VIc) or Formula (VId):

In other embodiments, the compound of Formula (VIc) or Formula (VId) hasa structure of Formula (VIIc) or (VIId):

In some embodiments, the compound of Formula (VIIc) or (VIId) has astructure of Formula (VIIIc) or (VIIId):

In some embodiments, the compounds of Formula (VIIIc) or (VIIId) has astructure of Formula (IXc) or (IXd):

In other embodiments, the compound of Formula (I) has a structure ofFormula (VIe) or Formula (VIf):

In other embodiments, the compound of Formula (VIe) or Formula (VIf) hasa structure of Formula (VIIe) or (VIIf):

In some embodiments of a compound of Formula (VIa), (VIIa), (VIIIa),(IXa), (VIc), (VIIc), (VIIIc), (IXc), (VIe), or (VIIe) R⁵ is selectedfrom alkyl, cycloalkyl, halo, aryl, and heteroaryl. For example, in someembodiments, R⁵ is selected from methyl, chloro, and pyrazolo.

In some embodiments of a compound of Formula (VIa), (VIb), (VIc), (VId),(VIe), (VIf), (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIIa),(VIIIb), (VIIIc), (VIIId), (IXa), (IXb), (IXc), or (IXd), W_(d) is:

wherein X₃ is CR¹³ or N; and R¹⁰, R¹¹, R¹², and R¹³ are as definedherein elsewhere.

In some embodiments, W_(d) is

wherein X₃ is as defined herein elsewhere, and R¹⁰ is hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″are taken together with nitrogen to form a cyclic moiety. For example,in some embodiments, R¹⁰ is amino or NR′R″, wherein R′ and R″ are takentogether with nitrogen to form a cyclic moiety.

In some embodiments, W_(d) is

wherein R¹⁰, R¹¹, and R¹² are as defined herein. For example, in someembodiments, W_(d) is

In other embodiments of a compound of Formula (VIa), (VIb), (VIc),(VId), (VIe), (VIf), (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf),(VIIIa), (VIIIb), (VIIIc), (VIIId), (IXa), (IXb), (IXc), or (IXd), W_(d)is:

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is C; and R¹⁰, R¹¹,R¹², and R¹³ are as defined herein elsewhere.

In some embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In other embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments of a compound of Formula (VIa), (VIb), (VIc), (VId),(VIe), (VIf), (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIIa),(VIIIb), (VIIIc), (VIIId), (IXa), (IXb), (IXc), or (IXd), W_(d) is

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is CR¹³; and R¹⁰,R¹¹, R¹², and R¹³ are as defined herein elsewhere.

In some embodiments, W_(d) is

For example, in one embodiment, W_(d) is

In some embodiments of a compound of Formula (VIa), (VIb), (VIc), (VId),(VIe), (VIf), (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIIa),(VIIIb), (VIIIc), (VIIId), (IXa), (IXb), (IXc), or (IXd), B is arylsubstituted with 0, 1, 2, or 3 occurrence(s) of R². For example, in someembodiments, B is phenyl substituted with 0, 1, 2, or 3 occurrence(s) ofR². In some embodiments of a compound of Formula (VIa), (VIb), (VIc),(VId), (VIe), (VIf), (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf),(VIIIa), (VIIIb), (VIIIc), (VIIId), (IXa), (IXb), (IXc), or (IXd), B isunsubstituted phenyl. In other embodiments of a compound of Formula(VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIIa), (VIIb), (VIIc),(VIId), (VIIe), (VIIf), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IXa),(IXb), (IXc), or (IXd), B is phenyl substituted with 1 occurrence of R².In some embodiments, R² is halo or alkyl. In other embodiments of acompound of Formula (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIIa),(VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIIa), (VIIIb), (VIIIc),(VIIId), (IXa), (IXb), (IXc), or (IXd), B is cycloalkyl or heterocyclyl.

In one embodiment, B is selected from the moieties presented in Table 1.

TABLE 1 Illustrative B moieties of the compounds described herein. Sub-class # B B-1

B-2

B-3 —CH(CH₃)₂ B-4

B-5

B-6

B-7

B-8

B-9

B-10

B-11

B-12

B-13

B-14

B-15

B-16

B-17

B-18

B-19

B-20

B-21

B-22

B-23

B-24

B-25

B-26

B-27

B-28

B-29

B-30

B-31

B-32

B-33

B-34

B-35

B-36

B-37

B-38

B-39

B-40

B-41

B-42

B-43

B-44

B-45

B-46

B-47

B-48

B-49

B-50

B-51

B-52

B-53

B-54

B-55

B-56

B-57

B-58

B-59

B-60

B-61

B-62

B-63

B-64

B-65

B-66

B-67

B-68

B-69

B-70

B-71

B-72

B-73

B-74

B-75

B-76

B-77

B-78

B-79

B-80

B-81

B-82

B-83

B-84

B-85

B-86

B-87 —CH₃ B-88 —CH₂CH₃ B-89

B-90

B-91

B-92

B-93

B-94

B-95

B-96

B-97

B-98

B-99

B-100

B-101

B-102

B-103

B-104

B-105

B-106

B-107

B-108

B-109

In some embodiments of a compound of Formula (I), B is aryl orheteroaryl substituted with 0 or 1 occurrence of R² and Cy is a 5- or6-membered aryl or heteroaryl group. For example, in some embodiments, Bis aryl substituted with 0 or 1 occurrence of R² and Cy is a 5- or6-membered aryl or heteroaryl group. In some embodiments, B is aryl orheteroaryl substituted with 0 or 1 occurrence of R² and Cy is a6-membered aryl group. In some embodiments, Cy is phenyl substitutedwith alkyl, fluoroalkyl, aryl, heteroaryl, or halo. In some embodimentsof a compound of Formula (I), B is aryl or heteroaryl substituted with 0or 1 occurrences of R², Cy is a 5- or 6-membered aryl or heteroarylgroup, X is —(CH(R⁹))_(z)—, and Y is —NHC(═O)—, wherein R⁹ is chosenindependently from hydrogen and alkyl. For example, in some embodiments,—X—Y— is —CH(CH₃)—NH—C(═O)—. In some embodiments, B is aryl substitutedwith 0 or 1 occurrence of R² and Cy is a 5- or 6-membered aryl orheteroaryl group. In another embodiment, B is aryl or heteroarylsubstituted with 0 or 1 occurrence of R² and Cy is a 6-membered arylgroup. In some embodiments, Cy is phenyl substituted with alkyl,fluoroalkyl, aryl, heteroaryl, or halo.

In another embodiment, provided herein are compounds of Formula (X) or(XI):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein:

W_(b) ⁵ is N, CHR⁸, or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0 or 1 occurrence of R³ and 0,1, 2, or 3 occurrence(s) of R⁵;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁵)—, —C(R¹⁵)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, orheteroalkyl;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R⁵ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate,or NR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety;

X is —(CH(R¹⁶))_(z)—;

Y is —N(R¹⁶)—C(═O)—, —C(═O)—N(R¹⁶), —C(═O)—N(R¹⁶)—(CHR¹⁶)—,—N(R¹⁶)—S(═O)—, or —N(R¹⁶)—S(═O)₂—;

z is an integer of 1, 2, 3, or 4;

each R¹⁶ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo, or heteroaryl; and

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which issubstituted with one or more R¹⁰, R¹¹, R¹², or R¹³; and

wherein R¹⁰, R¹¹, R¹², and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, W_(d) is

wherein

one of X₁ and X₂ is N and one of X₁ and X₂ is C or CR¹³;

X₃ is CR¹³ or N; and

R¹⁰, R¹¹, R¹², and R¹³ are as defined herein elsewhere.

In specific embodiments, W_(d) is

In specific embodiments, W_(d) is

wherein R¹⁰, R¹¹, and R¹² are as defined herein.

In specific embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments of a compound of Formula (X) or (XI), W_(d) is:

wherein X₃ is CR¹³ or N, and R¹⁰, R¹¹, R¹², and R¹³ are as definedherein elsewhere.

In some embodiments, W_(d) is

wherein R¹⁰ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate,urea, carbonate, or NR′R″ wherein R′ and R″ are taken together withnitrogen to form a cyclic moiety, and X₃ is as defined herein. Forexample, in some embodiments, R¹⁰ is amino or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In some embodiments, W_(d) is

wherein R¹⁰, R¹¹, and R¹² are as defined herein. For example, in someembodiments, W_(d) is

In other embodiments of a compound of Formula (X) or (XI), W_(d) is:

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is C; and R¹⁰, R¹¹,R¹², and R¹³ are as defined herein elsewhere. In some embodiments, W_(d)is

For example, in some embodiments, W_(d) is

In other embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments of a compound of Formula (X) or (XI), W_(d) is

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is CR¹³; and R¹⁰,R¹¹, R¹², and R¹³ are as defined herein elsewhere.

In some embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments, provided herein is a compound of Formula (X). Inone embodiment, the compound has the Formula:

In some embodiments, Cy is a 5- or 6-membered ring. In some embodiments,Cy is a 6-membered ring, such as a 6-membered aryl group. For instance,in some embodiments, Cy is a 6-membered ring, including, e.g.,unsubstituted or substituted phenyl. In one embodiment, W_(b) ⁵ is CH.In one embodiment, R¹⁰, R¹¹, R¹², and R¹³ are H.

In another embodiment, provided herein are compounds of Formula (XV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

W_(b) ⁵ is N, CHR⁸, or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0 or 1 occurrence of R³ and 0,1, 2, or 3 occurrence(s) of R¹⁷;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁵)—, —C(R¹⁵)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl,hydroxyl, or nitro;

each R¹⁷ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate,or NR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety;

X is —(CH(R⁹))_(z)—;

Y is —N(R⁹)—C(═O)—, —C(═O)—N(R⁹)—, —C(═O)—N(R⁹)—(CHR⁹)—, —N(R⁹)—S(═O)—,—S(═O)—N(R⁹)—, —S(═O)₂—N(R⁹)—, —N(R⁹)—C(═O)—N(R⁹)—, or —N(R⁹)—S(═O)₂—;

z is an integer of 1, 2, 3, or 4;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, orheteroalkyl;

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which issubstituted with one or more R¹⁰, R¹¹, R¹², or R¹³; and

wherein R¹⁰, R¹¹, R¹², and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety;

with the proviso that said compound is not

In some embodiments, the compound of Formula (XV) is a compound ofFormula (XVI):

In some embodiments, R³ is halo, alkyl, heteroalkyl, fluoroalkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocyclyl. For example,in some embodiments, R³ is alkyl or halo.

In some embodiments, n is 1 and L is —C(═O)—.

In some embodiments, R^(1′) is substituted alkyl, substituted nitrogen,or NR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety. For instance, in some embodiments, the cyclic moiety is aheterocyclic or heteroaryl group, such as, e.g., a morpholino group. Inother instances, R^(1′) is substituted alkyl, including alkyl which issubstituted with a heterocyclyl group.

In some embodiments, X is absent or is —(CH(R⁹))_(z)—. In someembodiments, X is —(CH(R⁹))_(z)—. In some embodiments, R⁹ is methyl orhydrogen. In some embodiments, z is 1. In some embodiments, X is —CH₂—or —CH(CH₃)—. In some embodiments, the carbon of the —CH(CH₃)— moietyhas an (S)-stereochemical configuration. Alternatively, the carbon ofthe —CH(CH₃)— moiety has an (R)-stereochemical configuration.

In some embodiments, Y is —N(H)—C(═O)—. In some embodiments, Y is—N(CH₃)—C(═O)—.

In some embodiments, —X—Y— is —CH₂—N(CH₃)—C(═O)—.

In some embodiments, —X—Y— is (S)—CH(CH₃)—NH—C(═O)—. Alternatively, insome embodiments, —X—Y— is (R)—CH(CH₃)—NH—C(═O)—.

In some embodiments, W_(d) is monocyclic heteroaryl. In someembodiments, W_(d) is:

wherein X₃ is CR¹³ or N; and R¹⁰, R¹¹, R¹², and R¹³ are as definedherein elsewhere.

In some embodiments, W_(d) is

wherein X₃, R¹⁰, R¹¹, and R¹² are as defined herein. For example, insome embodiments, W_(d) is

In some embodiments, W_(d) is a 5/6-bicyclic heteroaryl. In someembodiments, W_(d) is:

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is C; and R¹⁰, R¹¹,R¹², and R¹³ are as defined herein elsewhere. In some embodiments, W_(d)is

For example, in some embodiments, W_(d) is

In other embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments, R¹⁰ is H or methyl.

In some embodiments, W_(d) is a 6/6-bicyclic heteroaryl. In someembodiments, W_(d) is:

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is CR¹³; and R¹⁰,R¹¹, R¹², and R¹³ are as defined herein elsewhere. In some embodiments,W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments, Cy is aryl or heteroaryl group substituted by 0 or1 occurrence of R³ and 0, 1, 2, or 3 occurrence(s) of R¹⁷. In someembodiments, Cy is aryl substituted with 0 or 1 occurrence or R³ and 0,1, 2, or 3 occurrence(s) of R¹⁷. For example, in some embodiments, Cy isphenyl substituted with 1 occurrence of R³ and 0 occurrence of R¹⁷. Insome embodiments, Cy is phenyl substituted with 0 occurrence of R³ and 0occurrence of R¹⁷. In other embodiments, Cy is heteroaryl substitutedwith 0 or 1 occurrence of R³ and 0, 1, 2, or 3 occurrence(s) of R¹⁷. Insome embodiments, Cy can be, for example, pyridinyl, pyridazinyl,thiophenyl, furanyl, pyrrolyl, thiazolyl, or isothiazolyl. In someembodiments, Cy is 5-membered heteroaryl substituted with 0 or 1occurrence of R³ and 0, 1, 2, or 3 occurrence(s) of R¹⁷. In otherembodiments, Cy is 6-membered heteroaryl substituted with 0 or 1occurrence of R³ and 0, 1, 2, or 3 occurrence(s) of R¹⁷. In someembodiments, Cy is aryl, thiophenyl, or isothiazolyl. For example, insome embodiments, Cy is thiophenyl substituted with 0 occurrence of R³and 1 occurrence of R¹⁷. In some embodiments, Cy is isothiazolylsubstituted with 0 occurrence of R³ and 1 occurrence of R¹⁷.

In some embodiments of a compound of Formula (XV), R^(1′) is hydrogen,alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate,urea, carbonate, or NR′R″, wherein R′ and R″ are taken together withnitrogen to form a cyclic moiety.

In some embodiments of a compound of Formula (XV), R^(1′) is hydrogen,or unsubstituted or substituted alkyl (including, but not limited to,—CH₃, —CH₂CH₃, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl,pentyl, hexyl, and heptyl). In other embodiments, R^(1′) isunsubstituted or substituted alkenyl (including, but not limited to,unsubstituted or substituted C₂-C₅ alkenyl such as, for example, vinyl,allyl, 1-methyl propen-1-yl, butenyl, or pentenyl), or unsubstituted orsubstituted alkynyl (including, but not limited to, unsubstituted orsubstituted C₂-C₅ alkynyl such as, for example, acetylenyl, propargyl,butynyl, or pentynyl). Alternatively, in some embodiments, R^(1′) isunsubstituted or substituted aryl (including, but not limited to,monocyclic or bicyclic aryl), or unsubstituted or substituted arylalkyl(including, but not limited to, monocyclic or bicyclic aryl linked toalkyl, wherein alkyl includes, but is not limited to, —CH₃, —CH₂CH₃,n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some otherembodiments, R^(1′) is unsubstituted or substituted heteroaryl,including, but not limited to, monocyclic and bicyclic heteroaryl.Examples of monocyclic heteroaryl R^(1′) include, but are not limitedto, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl,pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl.Examples of bicyclic heteroaryl R^(1′) include, but are not limited to,benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl,pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl,pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl,imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

Also provided herein are compounds of Formula (XV), wherein R^(1′) isunsubstituted or substituted heteroarylalkyl, including, but not limitedto, monocyclic and bicyclic heteroaryl as described above, that arelinked to alkyl, which in turn includes, but is not limited to, —CH₃,—CH₂CH₃, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In someembodiments, R^(1′) is unsubstituted or substituted cycloalkyl(including, but not limited to, cyclopropyl, cyclobutyl, andcyclopentyl), or unsubstituted or substituted heteroalkyl (non-limitingexamples include ethoxymethyl, methoxymethyl, and diethylaminomethyl).In some further embodiments, R^(1′) is unsubstituted or substitutedheterocyclyl, which includes, but is not limited to, pyrrolidinyl,tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl,imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodimentsof a compound of Formula (XV), R^(1′) is unsubstituted or substitutedalkoxy, including, but not limited to, C₁-C₄ alkoxy, such as methoxy,ethoxy, propoxy, or butoxy. In some embodiments, R^(1′) is unsubstitutedor substituted heterocyclyloxy, including, but not limited to, 4-NHpiperidin-1-yl-oxy, 4-methyl-piperidin-1-yl-oxy,4-ethyl-piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, andpyrrolidin-3-yl-oxy. In other embodiments, R^(1′) is unsubstituted orsubstituted amino, wherein the substituted amino includes, but is notlimited to, dimethylamino, diethylamino, diisopropyl amino, N-methylN-ethyl amino, and dibutylamino. In some embodiments, R^(1′) isunsubstituted or substituted acyl, unsubstituted or substituted acyloxy(e.g., unsubstituted or substituted C₁-C₄ acyloxy), unsubstituted orsubstituted alkoxycarbonyl, unsubstituted or substituted amido, orunsubstituted or substituted sulfonamido. In other embodiments, R^(1′)is halo, selected from I, F, Cl, and Br. In some embodiments, R^(1′) isselected from cyano, hydroxyl, nitro, phosphate, urea, and carbonate. Insome embodiments, R^(1′) is —CH₃, —CH₂CH₃, n-propyl, isopropyl, n-butyl,tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH₃, —OCH₂CH₃, or —CF₃.

In some embodiments, R^(1′) of the compounds of Formula (XV) is NR′R″wherein R′ and R″ are taken together with the nitrogen to form a cyclicmoiety having from 3 to 8 ring atoms. In some embodiments, the cyclicmoiety so formed may further include one or more heteroatoms which areselected from S, O, and N. The cyclic moiety so formed is unsubstitutedor substituted, including, but not limited to, morpholinyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide,and thiomorpholinyl. Further non-limiting exemplary cyclic moietiesinclude, but are not limited to, the following:

Also provided herein are compounds of Formula (XV), wherein when R^(1′)is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocyclyl,heterocyclyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl,alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, or NR′R″(wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety), wherein R^(1′) is optionally substituted with one or more ofthe following substituents: alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, heterocyclyl, heterocyclyloxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy,alkoxycarbonyl, halo, cyano, hydroxyl, nitro, phosphate, urea,carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogento form a cyclic moiety. Each of the above substituents can be furthersubstituted with one or more substituents chosen from alkyl, alkoxy,amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano,hydroxyl, nitro, oxo, phosphate, urea, and carbonate.

For example, in one embodiment, provided herein are compounds whereinwhen R^(1′) is alkyl, the alkyl is substituted with NR′R″ wherein R′ andR″ are taken together with the nitrogen to form a cyclic moiety. Thecyclic moiety so formed can be unsubstituted or substituted.Non-limiting exemplary cyclic moieties include, but are not limited to,morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, andthiomorpholinyl. In other embodiments of a compound of Formula (XV),when R^(1′) is alkyl, the alkyl is substituted with heterocyclyl, whichincludes, but is not limited to, oxetanyl, azetidinyl,tetrahydrofuranyl, pyrrolyl, tetrahydropyranyl, piperidinyl,morpholinyl, and piperazinyl. All of the above listed heterocyclylsubstituents can be unsubstituted or substituted.

In yet other examples of a compound of Formula (XV), when R^(1′) isalkyl, the alkyl is substituted with a 5-, 6-, 7-, 8-, 9-, or10-membered monocyclic or bicyclic heteroaryl, which is unsubstituted orsubstituted. In some embodiments, examples of monocyclic heteroarylinclude, but are not limited to, pyrrolyl, thienyl, furyl, pyridinyl,pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl,pyrazolyl, and oxazolyl. In some embodiments, examples of bicyclicheteroaryl include, but are not limited to, benzothiophenyl, benzofuryl,indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl,pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl,pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, andpyrrolo[1,2-f][1,2,4]triazinyl.

In some embodiments of a compound of Formula (XV), L is —N(R¹⁵)—,wherein R¹⁵ is hydrogen, unsubstituted or substituted C₁-C₁₀ alkyl(which includes, but is not limited to, —CH₃, —CH₂CH₃, n-propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl),or unsubstituted or substituted C₃-C₇ cycloalkyl (which includes, but isnot limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).In other embodiments of a compound of Formula (XV), R¹⁵ is unsubstitutedor substituted heterocyclyl (which includes, but is not limited to,oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,piperidinyl, and piperazinyl), or unsubstituted or substituted C₂-C₁₀heteroalkyl (which includes, but is not limited to, methoxyethoxy,methoxymethyl, and diethylaminoethyl).

In some embodiments of a compound of Formula (XV), R¹ is —OR^(1′),wherein R^(1′) is hydrogen or alkyl. In one embodiment of a compound ofFormula (XV), R¹ is —O-alkyl, where alkyl is isopropyl.

In other embodiments of a compound of Formula (XV), R¹ is —NHR^(1′),—N(CH₃)R^(1′), —N(CH₂CH₃)R^(1′), —N(CH(CH₃)₂)R^(1′), or —OR^(1′),wherein R^(1′) is unsubstituted or substituted heterocyclyl(non-limiting examples thereof include 4-NH piperidin-1-yl,4-methyl-piperidin-1-yl, 4-ethyl-piperidin-1-yl,4-isopropyl-piperidin-1-yl, and pyrrolidin-3-yl), unsubstituted orsubstituted monocyclic aryl, or unsubstituted or substituted monocyclicheteroaryl (including, but not limited to, pyrrolyl, thienyl, furyl,pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl,thiazolyl, pyrazolyl, and oxazolyl). In one example, R¹ is —O-aryl,e.g., phenoxy. In another example, R¹ is —O-(4-methyl)piperidin-1-yl or—O-(4-isopropyl)piperidin-1-yl.

In some embodiments of a compound of Formula (XV), R^(1′) is an amidogroup of the formula

where R^(1″) and R^(1′″) are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl; or R^(1″) and R^(1′″) aretaken together with nitrogen to form a cyclic moiety.

Also provided herein are compounds of Formula (XV), wherein when R^(1′)is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocyclyl,heterocyclyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl,alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, or NR′R″(wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety), then R^(1′) is optionally substituted with an amido group ofthe formula:

where R^(1″) and R^(1′″) are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl; or R^(1″) and R^(1′″) aretaken together with nitrogen to form a cyclic moiety.

In one embodiment, when R^(1″) and R^(1′″) are taken together with thenitrogen to form a cyclic moiety, the cyclic moiety can have, forexample, from 3 to 8 ring atoms. In one embodiment, the cyclic moiety soformed can further include one or more heteroatoms which are selectedfrom S, O, and N. In some embodiments, the cyclic moiety so formed isunsubstituted or further substituted with hydrogen, alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano,hydroxyl, nitro, phosphate, urea, or carbonate.

In some embodiments of a compound of Formula (XV), R¹ is one of thefollowing moieties:

In some embodiments of a compound of Formula (XV), each R¹⁷ isindependently hydrogen, or unsubstituted or substituted alkyl(including, but not limited to, unsubstituted or substituted C₁-C₄alkyl). In some embodiments, each R¹⁷ is unsubstituted or substitutedalkenyl, including, but not limited to, unsubstituted or substitutedC₂-C₅ alkenyl. In some embodiments, each R¹⁷ is independentlyunsubstituted or substituted alkynyl, including, but not limited to,unsubstituted or substituted C₂-C₅ alkynyl. In some embodiments, eachR¹⁷ is independently unsubstituted or substituted cycloalkyl, including,but not limited to, unsubstituted or substituted C₃-C₅ cycloalkyl. Insome embodiments, each R¹⁷ is independently unsubstituted or substitutedheterocyclyl. In some embodiments, each R¹⁷ is independentlyunsubstituted or substituted heteroalkyl, including, but not limited to,unsubstituted or substituted C₁-C₄ heteroalkyl. In some embodiments,each R¹⁷ is independently unsubstituted or substituted alkoxy,including, but not limited to, unsubstituted or substituted C₁-C₄alkoxy. In some embodiments, each R¹⁷ is independently unsubstituted orsubstituted amido including, but not limited to, unsubstituted orsubstituted C₁-C₄ amido. In some embodiments, each R¹⁷ is independentlyunsubstituted or substituted amino. In some embodiments, each R¹⁷ isindependently unsubstituted or substituted acyl, unsubstituted orsubstituted acyloxy (e.g., unsubstituted or substituted C₁-C₄ acyloxy),unsubstituted or substituted alkoxycarbonyl, unsubstituted orsubstituted sulfonamido, or unsubstituted or substituted C₁-C₄sulfonamido. In some embodiments, each R¹⁷ is independently halo,selected from I, F, Cl, and Br. In some embodiments, each R¹⁷ isindependently selected from cyano, hydroxyl, and nitro. In some otherembodiments, each R¹⁷ is independently —CH₃, —CH₂CH₃, n-propyl,isopropyl, —OCH₃, —OCH₂CH₃, or —CF₃.

In some embodiments of a compound of Formula (XV), when R¹⁷ is alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino,acyloxy, alkoxycarbonyl, or sulfonamido, R¹⁷ is independently optionallysubstituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, or nitro,each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, or sulfonamido may itself be substituted.

In some embodiments of a compound of Formula (XV), no R¹⁷ are present.

In some embodiments of a compound of Formula (XV), X is absent. In otherembodiments of a compound of Formula (XV), X is —(CH(R⁹))_(z)—, and z isan integer of 1, 2, 3, or 4.

In some embodiments of a compound of Formula (XV), R⁹ is unsubstitutedor substituted alkyl, including, but not limited to, unsubstituted orsubstituted C₁-C₁₀ alkyl. In some embodiments, R⁹ is unsubstituted orsubstituted cycloalkyl, including, but not limited to, unsubstituted orsubstituted C₃-C₇ cycloalkyl. In some embodiments, R⁹ is ethyl, methyl,or hydrogen. In some embodiments, R⁹ is unsubstituted or substitutedheterocyclyl, including, but not limited to, unsubstituted orsubstituted C₂-C₁₀ heterocyclyl. In some embodiments, R⁹ isunsubstituted or substituted heteroalkyl including, but not limited to,unsubstituted or substituted C₂-C₁₀ heteroalkyl.

Also provided herein is a compound of Formula (XV) wherein R⁹ ishydrogen, and X is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or—CH(CH₂CH₃)—. In some embodiments, X is —(CH(R⁹))_(z)— wherein R⁹ is nothydrogen, and z is an integer of 1. When X is —CH(R⁹)— and R⁹ is nothydrogen, then the compound can adopt either an (S)- or(R)-stereochemical configuration with respect to the CH carbon. In someembodiments, the compound is a racemic mixture of (S)- and (R)-isomerswith respect to the CH carbon. In other embodiments, provided herein isa mixture of compounds of Formula (XV) wherein individual compounds ofthe mixture exist predominately in an (S)- or (R)-isomericconfiguration. For example, in one embodiment, the compound mixture hasan (S)-enantiomeric excess of greater than about 55%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,about 96%, about 97%, about 98%, about 99%, about 99.5%, or more at theCH carbon. In one embodiment, the compound mixture has an(S)-enantiomeric excess of greater than about 10%, greater than about20%, greater than about 30%, greater than about 40%, greater than about50%, greater than about 55%, greater than about 60%, greater than about65%, greater than about 70%, greater than about 75%, greater than about80%, greater than about 85%, greater than about 90%, greater than about95%, greater than about 96%, greater than about 97%, greater than about98%, greater than about 99%, greater than about 99.5%, or more, at theCH carbon. In other embodiments, the compound mixture has an(S)-enantiomeric excess of about 10% to about 99.5%, about 20% to about99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% toabout 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%,about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% toabout 99.5%, about 98% to about 99.5%, about 99% to about 99.5%, ormore, at the CH carbon.

In other embodiments of a compound of Formula (XV), the compound mixturehas an (R)-enantiomeric excess of greater than about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more,at the CH carbon. In one embodiment, the compound mixture has an(R)-enantiomeric excess of greater than about 10%, greater than about20%, greater than about 30%, greater than about 40%, greater than about50%, greater than about 55%, greater than about 60%, greater than about65%, greater than about 70%, greater than about 75%, greater than about80%, greater than about 85%, greater than about 90%, greater than about95%, greater than about 96%, greater than about 97%, greater than about98%, greater than about 99%, greater than about 99.5%, or more, at theCH carbon. In other embodiments, the compound mixture has an(R)-enantiomeric excess of about 10% to about 99.5%, about 20% to about99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% toabout 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%,about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% toabout 99.5%, about 98% to about 99.5%, about 99% to about 99.5%, ormore, at the CH carbon.

In some embodiments of a compound of Formula (XV), X is —CH(R⁹)— whereinR⁹ is methyl or ethyl, and the compound is an (S)-isomer.

In some embodiments of a compound of Formula (XV), Y is —N(R⁹)—(C═O)—wherein R⁹ is H or substituted or unsubstituted alkyl. For example, insome embodiments, Y is —N(H)—(C═O)—.

In some embodiments of a compound of Formula (XV), W_(d) is aryl,monocyclic heteroaryl, a 5/6-bicyclic heteroaryl, or a 6/6-bicyclicheteroaryl. For example, in some embodiments, W_(d) is:

wherein

one of X₁ and X₂ is N and one of X₁ and X₂ is C or CR¹³;

X₃ is CR¹³ or N; and

R¹⁰, R¹¹, R¹², and R¹³ are as defined herein elsewhere.

In some embodiments of a compound of Formula (XV), at least one of R¹⁰,R¹¹, R¹², and R¹³ is hydrogen, cyano, halo, unsubstituted or substitutedalkyl, unsubstituted or substituted alkynyl, or unsubstituted orsubstituted alkenyl. In some embodiments, at least one of R¹⁰, R¹¹, R¹²,and R¹³ is unsubstituted or substituted aryl. In some embodiments, atleast one of R¹⁰, R¹¹, R¹², and R¹³ is unsubstituted or substitutedheteroaryl, which includes, but is not limited to, heteroaryl having a5-membered ring; heteroaryl having a 6-membered ring; heteroaryl with atleast one nitrogen ring atom; heteroaryl with two nitrogen ring atoms;monocyclic heteroaryl; and bicyclic heteroaryl. In some embodiments, atleast one of R¹⁰, R¹¹, R¹², and R¹³ is unsubstituted or substitutedheterocyclyl, which includes, but is not limited to, heterocyclyl withone nitrogen ring atom, heterocyclyl with one oxygen ring atom,heterocyclyl with one sulfur ring atom, 5-membered heterocyclyl,6-membered heterocyclyl, saturated heterocyclyl, unsaturatedheterocyclyl, heterocyclyl having an unsaturated moiety connected to theheterocyclyl ring, heterocyclyl substituted by oxo, and heterocyclylsubstituted by two oxo. In some embodiments, at least one of R¹⁰, R¹¹,R¹², and R¹³ is unsubstituted or substituted cycloalkyl, including, butnot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloalkyl substituted by one oxo, and cycloalkyl having an unsaturatedmoiety connected to the cycloalkyl ring. In some embodiments, at leastone of R¹⁰, R¹¹, R¹², and R¹³ is unsubstituted or substituted amido,unsubstituted or substituted acyloxy, unsubstituted or substitutedalkoxycarbonyl, unsubstituted or substituted acyl, or unsubstituted orsubstituted sulfonamido.

In some embodiments, when at least one of R¹⁰, R¹¹, R¹², and R¹³ isalkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkoxycarbonyl, amido, acyloxy, acyl, or sulfonamido; each of which issubstituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl or nitro;each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, or sulfonamido may itself be substituted.

In some embodiments of a compound of Formula (XV), W_(d) is:

wherein X₃ is CR¹³ or N; and R¹⁰, R¹¹, R¹², and R¹³ are as definedherein elsewhere.

In some embodiments, W_(d) is

wherein R¹⁰ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate,urea, carbonate, or NR′R″ wherein R′ and R″ are taken together withnitrogen to form a cyclic moiety. For example, in some embodiments, R¹⁰is amino or NR′R″ wherein R′ and R″ are taken together with nitrogen toform a cyclic moiety.

In some embodiments, W_(d) is

wherein R¹⁰, R¹¹, and R¹² are as defined herein. For example, in someembodiments, W_(d) is

In other embodiments of a compound of Formula (XV), W_(d) is:

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is C; and R¹⁰, R¹¹,R¹², and R¹³ are as defined herein elsewhere. In some embodiments, W_(d)is

For example, in some embodiments, W_(d) is

In other embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments of a compound of Formula (XV), W_(d) is

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is CR¹³; and R¹⁰,R¹¹, R¹², and R¹³ are as defined herein elsewhere.

In some embodiments, W_(d) is

For example, in some embodiments, W_(d) is

In some embodiments of a compound of Formula (XV), the compound is:

wherein m is an integer of 0, 1, 2, or 3; and R¹, R¹⁷, X, Y, and W_(d)are as defined herein elsewhere.

In other embodiments, the compound of Formula (XV) has the structure:

wherein R¹, R³, X, Y, and W_(d) are as defined herein elsewhere.

In some embodiments, two adjacent occurrences of R⁹ together with theatoms to which they are attached form a 4- to 7-membered ring. In someembodiments, two adjacent occurrences of R⁹ together with the atoms towhich they are attached form a 5- to 6-membered ring.

In one embodiment, provided herein is a compound of Formula (XX):

wherein R³, B, and W_(d) are as defined herein elsewhere, e.g., asdefined for Formula (I).

In one embodiment, provided herein is a compound of Formula (XX-a) or(XX-b):

wherein R³, B, and W_(d) are as defined herein elsewhere, e.g., asdefined for Formula (I).

In one embodiment, provided herein is a compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein

Cy is aryl or heteroaryl substituted by 0 or 1 occurrence of R³ and 0,1, 2, or 3 occurrence(s) of R⁵;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4occurrence(s) of R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea, or carbonate;

X is —(CH(R⁹))_(z)—;

Y is —N(R⁹)—C(═O)—, —C(═O)—N(R⁹)—, —C(═O)—N(R⁹)—(CHR⁹)—, —N(R⁹)—S(═O)—,—S(═O)—N(R⁹)—, —S(═O)₂—N(R⁹)—, —N(R⁹)—C(═O)—N(R⁹)—, or —N(R⁹)—S(═O)₂—;

z is an integer of 1, 2, 3, or 4;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl,hydroxyl, or nitro;

each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, orheteroalkyl;

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which issubstituted with one or more R¹⁰, R¹¹, R¹², or R¹³, and

wherein R¹⁰, R¹¹, R¹², and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In some embodiments, one or more compounds described herein bind to aPI3 kinase (e.g., bind selectively). In some embodiments, one or morecompounds described herein bind selectively to a γ- or δ-subtype of aPI3 kinase. In some embodiments, one or more compounds described hereinbind selectively to a γ-subtype of a PI3 kinase. In some embodiments,one or more compounds described herein bind selectively to a δ-subtypeof a PI3 kinase.

In some embodiments, the IC₅₀ of a compound provided herein for p110α,p110β, p110γ, or p110δ is less than about 1 μM, less than about 100 nM,less than about 50 nM, less than about 10 nM, less than 1 nM, or evenless than about 0.5 nM. In some embodiments, the IC₅₀ of a compoundprovided herein for mTOR is less than about 1 μM, less than about 100nM, less than about 50 nM, less than about 10 nM, less than 1 nM, oreven less than about 0.5 nM. In some other embodiments, one or morecompounds provided herein exhibit dual binding specificity and arecapable of inhibiting a PI3 kinase (e.g., a class I PI3 kinase) as wellas a protein kinase (e.g., mTOR) with an IC₅₀ value less than about 1μM, less than about 100 nM, less than about 50 nM, less than about 10nM, less than 1 nM, or even less than about 0.5 nM. In some embodiments,one or more compounds provided herein are capable of inhibiting tyrosinekinases, including, for example, DNA-dependent protein kinase (Pubmedprotein accession number (PPAN) AAA79184), Abl tyrosine kinase (PPANCAA52387), Bcr-Abl, hemopoietic cell kinase (PPAN CAI19695), Src (PPANCAA24495), vascular endothelial growth factor receptor 2 (PPANABB82619), vascular endothelial growth factor receptor-2 (PPANABB82619), epidermal growth factor receptor (PPAN AG43241), EPH receptorB4 (PPAN EAL23820), stem cell factor receptor (PPAN AAF22141),tyrosine-protein kinase receptor TIE-2 (PPAN Q02858), fms-relatedtyrosine kinase 3 (PPAN NP_(—)004110), platelet-derived growth factorreceptor alpha (PPAN NP_(—)990080), RET (PPAN CAA73131), and functionalmutants thereof. In some embodiments, the tyrosine kinase is Abl,Bcr-Abl, EGFR, or Flt-3, or any other kinases listed herein.

In some embodiments, non-limiting exemplary compounds exhibit one ormore functional characteristics disclosed herein. For example, one ormore compounds provided herein bind specifically to a PI3 kinase. Insome embodiments, the IC₅₀ of a compound provided herein for p110α,p110β, p110γ, or p110δ is less than about 1 μM, less than about 100 nM,less than about 50 nM, less than about 10 nM, less than about 1 nM, lessthan about 0.5 nM, less than about 100 pM, or less than about 50 pM.

In some embodiments, one or more of the compounds provided herein canselectively inhibit one or more members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase) with an IC₅₀ value of about100 nM, about 50 nM, about 10 nM, about 5 nM, about 100 pM, about 10 pM,or about 1 pM, or less, as measured in an in vitro kinase assay.

In some embodiments, one or more of the compounds provided herein canselectively inhibit one or two members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase), such as, PI3-kinase α,PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some aspects, some ofthe compounds provided herein selectively inhibit PI3-kinase δ ascompared to all other type I PI3-kinases. In other aspects, some of thecompounds provided herein selectively inhibit PI3-kinase δ andPI3-kinase γ as compared to the rest of the type I PI3-kinases. In otheraspects, some of the compounds provided herein selectively inhibitPI3-kinase γ as compared to all other type I PI3-kinases. In yet otheraspects, some of the compounds provided herein selectively inhibitPI3-kinase α and PI3-kinase β as compared to the rest of the type IPI3-kinases. In still yet another aspect, some of the compounds providedherein selectively inhibit PI3-kinase δ and PI3-kinase α as compared tothe rest of the type I PI3-kinases. In still yet another aspect, some ofthe compounds provided herein selectively inhibit PI3-kinase γ andPI3-kinase α as compared to the rest of the type I PI3-kinases. In stillyet another aspect, some of the subject compounds selectively inhibitPI3-kinase δ and PI3-kinase β as compared to the rest of the type IPI3-kinases, or selectively inhibit PI3-kinase δ and PI3-kinase α ascompared to the rest of the type I PI3-kinases, or selectively inhibitPI3-kinase α and PI3-kinase γ as compared to the rest of the type IPI3-kinases, or selectively inhibit PI3-kinase γ and PI3-kinase β ascompared to the rest of the type I PI3-kinases.

In yet another aspect, an inhibitor that selectively inhibits one ormore members of type I PI3-kinases, or an inhibitor that selectivelyinhibits one or more type I PI3-kinase mediated signaling pathways,alternatively can be understood to refer to a compound that exhibits a50% inhibitory concentration (IC₅₀) with respect to a given type IPI3-kinase, that is at least about 10-fold, at least about 20-fold, atleast about 50-fold, at least about 100-fold, at least about 200-fold,at least about 500-fold, at least about 1000-fold, at least about2000-fold, at least about 5000-fold, or at least about 10,000-fold,lower than the inhibitor's IC₅₀ with respect to the rest of the othertype I PI3-kinases. In one embodiment, an inhibitor selectively inhibitsPI3-kinase δ as compared to PI3-kinase β with at least about 10-foldlower IC₅₀ for PI3-kinase δ. In certain embodiments, the IC₅₀ forPI3-kinase δ is below about 100 nM, while the IC₅₀ for PI3-kinase β isabove about 1000 nM. In certain embodiments, the IC₅₀ for PI3-kinase δis below about 50 nM, while the IC₅₀ for PI3-kinase β is above about5000 nM. In certain embodiments, the IC₅₀ for PI3-kinase δ is belowabout 10 nM, while the IC₅₀ for PI3-kinase β is above about 1000 nM,above about 5,000 nM, or above about 10,000 nM. In one embodiment, aninhibitor selectively inhibits PI3-kinase γ as compared to PI3-kinase βwith at least about 10-fold lower IC₅₀ for PI3-kinase γ. In certainembodiments, the IC₅₀ for PI3-kinase γ is below about 100 nM, while theIC₅₀ for PI3-kinase β is above about 1000 nM. In certain embodiments,the IC₅₀ for PI3-kinase γ is below about 50 nM, while the IC₅₀ forPI3-kinase β is above about 5000 nM. In certain embodiments, the IC₅₀for PI3-kinase γ is below about 10 nM, while the IC₅₀ for PI3-kinase βis above about 1000 nM, above about 5,000 nM, or above about 10,000 nM.

Pharmaceutical Compositions

In some embodiments, provided herein are pharmaceutical compositionscomprising a compound as disclosed herein, or an enantiomer, a mixtureof enantiomers, or a mixture of two or more diastereomers thereof, or apharmaceutically acceptable form thereof (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives), and a pharmaceutically acceptableexcipient, diluent, or carrier, including inert solid diluents andfillers, sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers and adjuvants. In some embodiments, apharmaceutical composition described herein includes a second activeagent such as an additional therapeutic agent, (e.g., achemotherapeutic).

1. Formulations

Pharmaceutical compositions can be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets (e.g., those targeted forbuccal, sublingual, and systemic absorption), capsules, boluses,powders, granules, pastes for application to the tongue, andintraduodenal routes; parenteral administration, including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion as, for example, a sterile solution orsuspension, or sustained-release formulation; topical application, forexample, as a cream, ointment, or a controlled-release patch or sprayapplied to the skin; intravaginally or intrarectally, for example, as apessary, cream, stent or foam; sublingually; ocularly; pulmonarily;local delivery by catheter or stent; intrathecally, or nasally.

Examples of suitable aqueous and nonaqueous carriers which can beemployed in pharmaceutical compositions include water, ethanol, polyols(such as glycerol, propylene glycol, polyethylene glycol, and the like),and suitable mixtures thereof, vegetable oils, such as olive oil, andinjectable organic esters, such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of coating materials, such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservatives,wetting agents, emulsifying agents, dispersing agents, lubricants,and/or antioxidants. Prevention of the action of microorganisms upon thecompounds described herein can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It can also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form can be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound described herein and/or thechemotherapeutic with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound as disclosed herein withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Preparations for such pharmaceutical compositions are well-known in theart. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, WilliamG, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill,2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, New York, 1990; Katzung, ed., Basic and ClinicalPharmacology, Twelfth Edition, McGraw Hill, 2011; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety. Exceptinsofar as any conventional excipient medium is incompatible with thecompounds provided herein, such as by producing any undesirablebiological effect or otherwise interacting in a deleterious manner withany other component(s) of the pharmaceutically acceptable composition,the excipient's use is contemplated to be within the scope of thisdisclosure.

In some embodiments, the concentration of one or more of the compoundsprovided in the disclosed pharmaceutical compositions is less than about100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%,about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%,about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%,about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%,about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%,about 0.0002%, or about 0.0001%, w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is greater than about 90%, about 80%, about 70%,about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%,about 19.50%, about 19.25%, about 19%, about 18.75%, about 18.50%, about18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%,about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%,about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about11.50%, about 11.25%, about 11%, about 10.75%, about 10.50%, about10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%,about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%,about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%,about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%,about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%,about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001%, w/w, w/v,or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is in the range from approximately 0.0001% toapproximately 50%, approximately 0.001% to approximately 40%,approximately 0.01% to approximately 30%, approximately 0.02% toapproximately 29%, approximately 0.03% to approximately 28%,approximately 0.04% to approximately 27%, approximately 0.05% toapproximately 26%, approximately 0.06% to approximately 25%,approximately 0.07% to approximately 24%, approximately 0.08% toapproximately 23%, approximately 0.09% to approximately 22%,approximately 0.1% to approximately 21%, approximately 0.2% toapproximately 20%, approximately 0.3% to approximately 19%,approximately 0.4% to approximately 18%, approximately 0.5% toapproximately 17%, approximately 0.6% to approximately 16%,approximately 0.7% to approximately 15%, approximately 0.8% toapproximately 14%, approximately 0.9% to approximately 12%, orapproximately 1% to approximately 10%, w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is in the range from approximately 0.001% toapproximately 10%, approximately 0.01% to approximately 5%,approximately 0.02% to approximately 4.5%, approximately 0.03% toapproximately 4%, approximately 0.04% to approximately 3.5%,approximately 0.05% to approximately 3%, approximately 0.06% toapproximately 2.5%, approximately 0.07% to approximately 2%,approximately 0.08% to approximately 1.5%, approximately 0.09% toapproximately 1%, or approximately 0.1% to approximately 0.9%, w/w, w/vor v/v.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is equal to or less than about 10 g, about 9.5 g, about9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g,about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g,about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g,about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g,about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g,about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g,about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about0.0001 g.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is more than about 0.0001 g, about 0.0002 g, about0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g,about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g,about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g,about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g,about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g,about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g,about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g,about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is in the range of about 0.0001 to about 10 g, about0.0005 to about 9 g, about 0.001 to about 8 g, about 0.005 to about 7 g,about 0.01 to about 6 g, about 0.05 to about 5 g, about 0.1 to about 4g, about 0.5 to about 4 g, or about 1 to about 3 g.

1A. Formulations for Oral Administration

In some embodiments, provided herein are pharmaceutical compositions fororal administration containing a compound as disclosed herein, and apharmaceutical excipient suitable for oral administration. In someembodiments, provided herein are pharmaceutical compositions for oraladministration containing: (i) an effective amount of a disclosedcompound; optionally (ii) an effective amount of one or more secondagents; and (iii) one or more pharmaceutical excipients suitable fororal administration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition can be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions suitable for oral administration can be presented asdiscrete dosage forms, such as capsules, cachets, or tablets, or liquidsor aerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion. Such dosage forms can be prepared by anyof the methods of pharmacy, but all methods include the step of bringingthe active ingredient into association with the carrier, whichconstitutes one or more ingredients. In general, the pharmaceuticalcompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the pharmaceutical compositions for an oral dosage form, anyof the usual pharmaceutical media can be employed as carriers, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, in someembodiments without employing the use of lactose. For example, suitablecarriers include powders, capsules, and tablets, with the solid oralpreparations. In some embodiments, tablets can be coated by standardaqueous or nonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants can be used in the pharmaceutical compositions as providedherein to provide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant can produce tablets which candisintegrate in the bottle. Too little can be insufficient fordisintegration to occur and can thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) canbe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used can vary based upon the type of formulationand mode of administration, and can be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, canbe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms include, butare not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein can be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, forexample, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, hydrophilic surfactants,lipophilic surfactants, and mixtures thereof. That is, a mixture ofhydrophilic surfactants can be employed, a mixture of lipophilicsurfactants can be employed, or a mixture of at least one hydrophilicsurfactant and at least one lipophilic surfactant can be employed.

A suitable hydrophilic surfactant can generally have an HLB value of atleast about 10, while suitable lipophilic surfactants can generally havean HLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants can be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants can be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants can include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids, and sterols; polyoxyethylene sterols, derivatives, and analoguesthereof; polyoxyethylated vitamins and derivatives thereof;polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof;polyethylene glycol sorbitan fatty acid esters and hydrophilictransesterification products of a polyol with at least one member oftriglycerides, vegetable oils, and hydrogenated vegetable oils. Thepolyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol,propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate,sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octylphenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids and sterols; oil-soluble vitamins/vitamin derivatives; andmixtures thereof. Within this group, non-limiting examples of lipophilicsurfactants include glycerol fatty acid esters, propylene glycol fattyacid esters, and mixtures thereof, or are hydrophobictransesterification products of a polyol with at least one member ofvegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the pharmaceutical composition can include asolubilizer to ensure good solubilization and/or dissolution of acompound as provided herein and to minimize precipitation of thecompound. This can be especially important for pharmaceuticalcompositions for non-oral use, e.g., pharmaceutical compositions forinjection. A solubilizer can also be added to increase the solubility ofthe hydrophilic drug and/or other components, such as surfactants, or tomaintain the pharmaceutical composition as a stable or homogeneoussolution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers can also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. In someembodiments, solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer can be limited to abioacceptable amount, which can be readily determined by one of skill inthe art. In some circumstances, it can be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the pharmaceutical composition toa subject using conventional techniques, such as distillation orevaporation. Thus, if present, the solubilizer can be in a weight ratioof about 10%, 25%, 50%, 100%, or up to about 200% by weight, based onthe combined weight of the drug, and other excipients. If desired, verysmall amounts of solubilizer can also be used, such as about 5%, 2%, 1%or even less. Typically, the solubilizer can be present in an amount ofabout 1% to about 100%, more typically about 5% to about 25% by weight.

The pharmaceutical composition can further include one or morepharmaceutically acceptable additives and excipients. Such additives andexcipients include, without limitation, detackifiers, anti-foamingagents, buffering agents, polymers, antioxidants, preservatives,chelating agents, viscomodulators, tonicifiers, flavorants, colorants,oils, odorants, opacifiers, suspending agents, binders, fillers,plasticizers, lubricants, and mixtures thereof.

Exemplary preservatives can include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives. Exemplaryantioxidants include, but are not limited to, alpha tocopherol, ascorbicacid, acorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, monothioglycerol, potassium metabisulfite, propionicacid, propyl gallate, sodium ascorbate, sodium bisulfite, sodiummetabisulfite, and sodium sulfite. Exemplary chelating agents includeethylenediaminetetraacetic acid (EDTA), citric acid monohydrate,disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malicacid, phosphoric acid, sodium edetate, tartaric acid, and trisodiumedetate. Exemplary antimicrobial preservatives include, but are notlimited to, benzalkonium chloride, benzethonium chloride, benzylalcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine,chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol,glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.Exemplary antifungal preservatives include, but are not limited to,butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoicacid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodiumbenzoate, sodium propionate, and sorbic acid. Exemplary alcoholpreservatives include, but are not limited to, ethanol, polyethyleneglycol, phenol, phenolic compounds, bisphenol, chlorobutanol,hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservativesinclude, but are not limited to, vitamin A, vitamin C, vitamin E,betacarotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid. Other preservatives include, but arenot limited to, tocopherol, tocopherol acetate, deteroxime mesylate,cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened(BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ethersulfate (SLES), sodium bisulfite, sodium metabisulfite, potassiumsulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben,Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certainembodiments, the preservative is an antioxidant. In other embodiments,the preservative is a chelating agent.

Exemplary oils include, but are not limited to, almond, apricot kernel,avocado, babassu, bergamot, black current seed, borage, cade, camomile,canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, codliver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose,fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop,isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon,litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink,nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel,peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary,safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, sheabutter, silicone, soybean, sunflower, tea tree, thistle, tsubaki,vetiver, walnut, and wheat germ oils. Exemplary oils include, but arenot limited to, butyl stearate, caprylic triglyceride, caprictriglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,silicone oil, and combinations thereof.

In addition, an acid or a base can be incorporated into thepharmaceutical composition to facilitate processing, to enhancestability, or for other reasons. Examples of pharmaceutically acceptablebases include amino acids, amino acid esters, ammonium hydroxide,potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesiumaluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite,magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine,ethylenediamine, triethanolamine, triethylamine, triisopropanolamine,trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.Also suitable are bases that are salts of a pharmaceutically acceptableacid, such as acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonicacid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearicacid, succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid, uric acid, and the like. Salts of polyproticacids, such as sodium phosphate, disodium hydrogen phosphate, and sodiumdihydrogen phosphate can also be used. When the base is a salt, thecation can be any convenient and pharmaceutically acceptable cation,such as ammonium, alkali metals, alkaline earth metals, and the like.Examples can include, but not limited to, sodium, potassium, lithium,magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

1B. Formulations for Parenteral Administration

In some embodiments, provided herein are pharmaceutical compositions forparenteral administration containing a compound as disclosed herein, anda pharmaceutical excipient suitable for parenteral administration. Insome embodiments, provided herein are pharmaceutical compositions forparenteral administration containing: (i) an effective amount of adisclosed compound; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor parenteral administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

The forms in which the disclosed pharmaceutical compositions can beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils can also be employed.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils can also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compound asdisclosed herein in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as appropriate, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the appropriateother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, certainmethods of preparation are vacuum-drying and freeze-drying techniqueswhich yield a powder of the active ingredient plus any additionalingredient from a previously sterile-filtered solution thereof.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use. Injectable compositions can contain from about 0.1to about 5% w/w of a compound as disclosed herein.

1C. Formulations for Topical Administration

In some embodiments, provided herein are pharmaceutical compositions fortopical (e.g., transdermal) administration containing a compound asdisclosed herein, and a pharmaceutical excipient suitable for topicaladministration. In some embodiments, provided herein are pharmaceuticalcompositions for topical administration containing: (i) an effectiveamount of a disclosed compound; optionally (ii) an effective amount ofone or more second agents; and (iii) one or more pharmaceuticalexcipients suitable for topical administration. In some embodiments, thepharmaceutical composition further contains: (iv) an effective amount ofa third agent.

Pharmaceutical compositions provided herein can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationcan provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the disclosed methods employstransdermal delivery devices (“patches”). Such transdermal patches canbe used to provide continuous or discontinuous infusion of a compound asprovided herein in controlled amounts, either with or without anotheragent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Suitable devices for use in delivering intradermal pharmaceuticallyacceptable compositions described herein include short needle devicessuch as those described in U.S. Pat. Nos. 4,886,499; 5,190,521;5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662.Intradermal compositions can be administered by devices which limit theeffective penetration length of a needle into the skin, such as thosedescribed in PCT publication WO 99/34850 and functional equivalentsthereof. Jet injection devices which deliver liquid vaccines to thedermis via a liquid jet injector and/or via a needle which pierces thestratum corneum and produces a jet which reaches the dermis aresuitable. Jet injection devices are described, for example, in U.S. Pat.Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Topically-administrable formulations can, for example, comprise fromabout 1% to about 10% (w/w) of a compound provided herein relative tothe total weight of the formulation, although the concentration of thecompound provided herein in the formulation can be as high as thesolubility limit of the compound in the solvent. In some embodiments,topically-administrable formulations can, for example, comprise fromabout 1% to about 9% (w/w) of a compound provided herein, such as fromabout 1% to about 8% (w/w), further such as from about 1% to about 7%(w/w), further such as from about 1% to about 6% (w/w), further such asfrom about 1% to about 5% (w/w), further such as from about 1% to about4% (w/w), further such as from about 1% to about 3% (w/w), and furthersuch as from about 1% to about 2% (w/w) of a compound provided herein.Formulations for topical administration can further comprise one or moreof the additional pharmaceutically acceptable excipients describedherein.

1D. Formulations for Inhalation Administration

In some embodiments, provided herein are pharmaceutical compositions forinhalation administration containing a compound as disclosed herein, anda pharmaceutical excipient suitable for topical administration. In someembodiments, provided herein are pharmaceutical compositions forinhalation administration containing: (i) an effective amount of adisclosed compound; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor inhalation administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

Pharmaceutical compositions for inhalation or insufflation includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidpharmaceutical compositions can contain suitable pharmaceuticallyacceptable excipients as described herein. In some embodiments, thepharmaceutical compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Pharmaceuticalcompositions in pharmaceutically acceptable solvents can be nebulized byuse of inert gases. Nebulized solutions can be inhaled directly from thenebulizing device or the nebulizing device can be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder pharmaceutical compositions can beadministered, e.g., orally or nasally, from devices that deliver theformulation in an appropriate manner.

1E. Formulations for Ocular Administration

In some embodiments, the disclosure provides a pharmaceuticalcomposition for treating ophthalmic disorders. The pharmaceuticalcomposition can contain an effective amount of a compound as disclosedherein and a pharmaceutical excipient suitable for ocularadministration. Pharmaceutical compositions suitable for ocularadministration can be presented as discrete dosage forms, such as dropsor sprays each containing a predetermined amount of an active ingredienta solution, or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Otheradministration forms include intraocular injection, intravitrealinjection, topically, or through the use of a drug eluting device,microcapsule, implant, or microfluidic device. In some cases, thecompounds as disclosed herein are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film. It is contemplated that all localroutes to the eye can be used including topical, subconjunctival,periocular, retrobulbar, subtenon, intracameral, intravitreal,intraocular, subretinal, juxtascleral and suprachoroidal administration.Systemic or parenteral administration can be feasible including, but notlimited to intravenous, subcutaneous, and oral delivery. An exemplarymethod of administration will be intravitreal or subtenon injection ofsolutions or suspensions, or intravitreal or subtenon placement ofbioerodible or non-bioerodible devices, or by topical ocularadministration of solutions or suspensions, or posterior juxtascleraladministration of a gel or cream formulation.

Eye drops can be prepared by dissolving the active ingredient in asterile aqueous solution such as physiological saline, bufferingsolution, etc., or by combining powder compositions to be dissolvedbefore use. Other vehicles can be chosen, as is known in the art,including, but not limited to: balance salt solution, saline solution,water soluble polyethers such as polyethyene glycol, polyvinyls, such aspolyvinyl alcohol and povidone, cellulose derivatives such asmethylcellulose and hydroxypropyl methylcellulose, petroleum derivativessuch as mineral oil and white petrolatum, animal fats such as lanolin,polymers of acrylic acid such as carboxypolymethylene gel, vegetablefats such as peanut oil and polysaccharides such as dextrans, andglycosaminoglycans such as sodium hyaluronate. In some embodiments,additives ordinarily used in the eye drops can be added. Such additivesinclude isotonizing agents (e.g., sodium chloride, etc.), buffer agent(e.g., boric acid, sodium monohydrogen phosphate, sodium dihydrogenphosphate, etc.), preservatives (e.g., benzalkonium chloride,benzethonium chloride, chlorobutanol, etc.), thickeners (e.g.,saccharide such as lactose, mannitol, maltose, etc.; e.g., hyaluronicacid or its salt such as sodium hyaluronate, potassium hyaluronate,etc.; e.g., mucopolysaccharide such as chondroitin sulfate, etc.; e.g.,sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate,polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose or other agents known to those skilled in theart).

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic surfactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent is analkylamine, a tertiary alkyl amine, a quarternary ammonium compound, acationic lipid, an amino alcohol, a biguanidine salt, a cationiccompound or a mixture thereof. In some cases, the cationic agent is abiguanidine salt such as chlorhexidine, polyaminopropyl biguanidine,phenformin, alkylbiguanidine, or a mixture thereof. In some cases, thequaternary ammonium compound is a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, rnyristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof. Insome cases, the oil phase is mineral oil and light mineral oil, mediumchain triglycerides (MCT), coconut oil; hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

1F. Formulations for Controlled Release Administration

In some embodiments, provided herein are pharmaceutical compositions forcontrolled release administration containing a compound as disclosedherein, and a pharmaceutical excipient suitable for controlled releaseadministration. In some embodiments, provided herein are pharmaceuticalcompositions for controlled release administration containing: (i) aneffective amount of a disclosed compound; optionally (ii) an effectiveamount of one or more second agents; and (iii) one or morepharmaceutical excipients suitable for controlled releaseadministration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

Active agents such as the compounds provided herein can be administeredby controlled release means or by delivery devices that are well knownto those of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566;5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855;6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970;6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 each ofwhich is incorporated herein by reference. Such dosage forms can be usedto provide slow or controlled release of one or more active agentsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. Thus, the pharmaceuticalcompositions provided encompass single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps, and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. In some embodiments, the use of a controlled releasepreparation in medical treatment is characterized by a minimum of drugsubstance being employed to cure or control the disease, disorder, orcondition in a minimum amount of time. Advantages of controlled releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased subject compliance. In addition, controlledrelease formulations can be used to affect the time of onset of actionor other characteristics, such as blood levels of the drug, and can thusaffect the occurrence of side (e.g., adverse) effects.

In some embodiments, controlled release formulations are designed toinitially release an amount of a compound as disclosed herein thatpromptly produces the desired therapeutic effect, and gradually andcontinually release other amounts of the compound to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In order to maintain this constant level of the compound in the body,the compound should be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled release of an active agent can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

In certain embodiments, the pharmaceutical composition can beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump can be used (see, Sefton, CRC Crit. Ref. Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N.Engl. J. Med. 321:574 (1989)). In another embodiment, polymericmaterials can be used. In yet another embodiment, a controlled releasesystem can be placed in a subject at an appropriate site determined by apractitioner of skill, e.g., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, 115-138 (vol. 2, 1984). Other controlled release systems arediscussed in the review by Langer, Science 249:1527-1533 (1990). The oneor more active agents can be dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The one or more active agents then diffuse through the outer polymericmembrane in a release rate controlling step. The percentage of activeagent in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

2. Dosage

A compound described herein can be delivered in the form ofpharmaceutically acceptable compositions which comprise atherapeutically effective amount of one or more compounds describedherein and/or one or more additional therapeutic agents such as achemotherapeutic, formulated together with one or more pharmaceuticallyacceptable excipients. In some instances, the compound described hereinand the additional therapeutic agent are administered in separatepharmaceutical compositions and can (e.g., because of different physicaland/or chemical characteristics) be administered by different routes(e.g., one therapeutic is administered orally, while the other isadministered intravenously). In other instances, the compound describedherein and the additional therapeutic agent can be administeredseparately, but via the same route (e.g., both orally or bothintravenously). In still other instances, the compound described hereinand the additional therapeutic agent can be administered in the samepharmaceutical composition.

The selected dosage level will depend upon a variety of factorsincluding, for example, the activity of the particular compoundemployed, the route of administration, the time of administration, therate of excretion or metabolism of the particular compound beingemployed, the rate and extent of absorption, the duration of thetreatment, other drugs, compounds and/or materials used in combinationwith the particular compound employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

In general, a suitable daily dose of a compound described herein and/ora chemotherapeutic will be that amount of the compound which, in someembodiments, can be the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed herein. Generally, doses of the compounds described herein fora patient, when used for the indicated effects, will range from about0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg perday, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about100 mg per day, or about 0.0001 mg to about 500 mg per day, or about0.001 mg to about 500 mg per day, or about 0.01 mg to 1000 mg, or about0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg perday, or about 1 mg to 50 mg per day, or about 5 mg to 40 mg per day. Anexemplary dosage is about 10 to 30 mg per day. In some embodiments, fora 70 kg human, a suitable dose would be about 0.05 to about 7 g/day,such as about 0.05 to about 2.5 g/day. Actual dosage levels of theactive ingredients in the pharmaceutical compositions described hereincan be varied so as to obtain an amount of the active ingredient whichis effective to achieve the desired therapeutic response for aparticular patient, composition, and mode of administration, withoutbeing toxic to the patient. In some instances, dosage levels below thelower limit of the aforesaid range can be more than adequate, while inother cases still larger doses can be employed without causing anyharmful side effect, e.g., by dividing such larger doses into severalsmall doses for administration throughout the day.

In some embodiments, the compounds can be administered daily, everyother day, three times a week, twice a week, weekly, or bi-weekly. Thedosing schedule can include a “drug holiday,” e.g., the drug can beadministered for two weeks on, one week off, or three weeks on, one weekoff, or four weeks on, one week off, etc., or continuously, without adrug holiday. The compounds can be administered orally, intravenously,intraperitoneally, topically, transdermally, intramuscularly,subcutaneously, intranasally, sublingually, or by any other route.

In some embodiments, a compound as provided herein is administered inmultiple doses. Dosing can be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing canbe about once a month, about once every two weeks, about once a week, orabout once every other day. In another embodiment, a compound asdisclosed herein and another agent are administered together from aboutonce per day to about 6 times per day. In another embodiment, theadministration of a compound as provided herein and an agent continuesfor less than about 7 days. In yet another embodiment, theadministration continues for more than about 6 days, about 10 days,about 14 days, about 28 days, about two months, about six months, orabout one year. In some cases, continuous dosing is achieved andmaintained as long as necessary.

Administration of the pharmaceutical compositions as disclosed hereincan continue as long as necessary. In some embodiments, an agent asdisclosed herein is administered for more than about 1, about 2, about3, about 4, about 5, about 6, about 7, about 14, or about 28 days. Insome embodiments, an agent as disclosed herein is administered for lessthan about 28, about 14, about 7, about 6, about 5, about 4, about 3,about 2, or about 1 day. In some embodiments, an agent as disclosedherein is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

Since the compounds described herein can be administered in combinationwith other treatments (such as additional chemotherapeutics, radiationor surgery), the doses of each agent or therapy can be lower than thecorresponding dose for single-agent therapy. The dose for single-agenttherapy can range from, for example, about 0.0001 to about 200 mg, orabout 0.001 to about 100 mg, or about 0.01 to about 100 mg, or about 0.1to about 100 mg, or about 1 to about 50 mg per kilogram of body weightper day.

When a compound provided herein, is administered in a pharmaceuticalcomposition that comprises one or more agents, and the agent has ashorter half-life than the compound provided herein unit dose forms ofthe agent and the compound provided herein can be adjusted accordingly.

3. Kits

In some embodiments, provided herein are kits. The kits can include acompound or pharmaceutical composition as described herein, in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies, listing of side effects, and the like.Such kits can also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the pharmaceutical composition, and/orwhich describe dosing, administration, side effects, drug interactions,or other information useful to the health care provider. Suchinformation can be based on the results of various studies, for example,studies using experimental animals involving in vivo models and studiesbased on human clinical trials.

In some embodiments, a memory aid is provided with the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several tablets or capsules to betaken on a given day.

The kit can further contain another agent. In some embodiments, thecompound as disclosed herein and the agent are provided as separatepharmaceutical compositions in separate containers within the kit. Insome embodiments, the compound as disclosed herein and the agent areprovided as a single pharmaceutical composition within a container inthe kit. Suitable packaging and additional articles for use (e.g.,measuring cup for liquid preparations, foil wrapping to minimizeexposure to air, and the like) are known in the art and can be includedin the kit. In other embodiments, kits can further comprise devices thatare used to administer the active agents. Examples of such devicesinclude, but are not limited to, syringes, drip bags, patches, andinhalers. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits can also, in some embodiments,be marketed directly to the consumer.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. The strength of the sheet is such that the tablets or capsulescan be removed from the blister pack by manually applying pressure onthe recesses whereby an opening is formed in the sheet at the place ofthe recess. The tablet or capsule can then be removed via said opening.

Kits can further comprise pharmaceutically acceptable vehicles that canbe used to administer one or more active agents. For example, if anactive agent is provided in a solid form that must be reconstituted forparenteral administration, the kit can comprise a sealed container of asuitable vehicle in which the active agent can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Therapeutic Methods

Phosphoinositide 3-kinases (PI3Ks) are members of a conserved family oflipid kinases that regulate numerous cell functions, includingproliferation, differentiation, cell survival and metabolism. Severalclasses of PI3Ks exist in mammalian cells, including Class IA subgroup(e.g., PI3K-α, β, δ), which are generally activated by receptor tyrosinekinases (RTKs); Class IB (e.g., PI3K-γ), which is activated by G-proteincoupled receptors (GPCRs), among others. PI3Ks exert their biologicalactivities via a “PI3K-mediated signaling pathway” that includes severalcomponents that directly and/or indirectly transduce a signal triggeredby a PI3K, including the generation of second messengerphosphotidylinositol, 3,4,5-triphosphate (PIP3) at the plasma membrane,activation of heterotrimeric G protein signaling, and generation offurther second messengers such as cAMP, DAG, and IP3, all of which leadsto an extensive cascade of protein kinase activation (reviewed inVanhaesebroeck, B. et al. (2001) Annu Rev Biochem. 70:535-602). Forexample, PI3K-δ is activated by cellular receptors through interactionbetween the PI3K regulatory subunit (p85) SH2 domains, or through directinteraction with RAS. PIP3 produced by PI3K activates effector pathwaysdownstream through interaction with plextrin homology (PH) domaincontaining enzymes (e.g., PDK-1 and AKT [PKB]). (Fung-Leung W P. (2011)Cell Signal. 23(4):603-8). Unlike PI3K-δ, PI3K-γ is not associated witha regulatory subunit of the p85 family, but rather with a regulatorysubunit in the p101 family. PI3K-γ is associated with GPCRs, and isresponsible for the very rapid induction of PIP3. PI3K-γ can be alsoactivated by RAS.

In some embodiments, provided herein are methods of modulating a PI3Kkinase activity (e.g., selectively modulating) by contacting the kinasewith an effective amount of a compound as provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein. Modulation can be inhibition (e.g., reduction) or activation(e.g., enhancement) of kinase activity. In some embodiments, providedherein are methods of inhibiting kinase activity by contacting thekinase with an effective amount of a compound as provided herein insolution. In some embodiments, provided herein are methods of inhibitingthe kinase activity by contacting a cell, tissue, organ that express thekinase of interest, with a compound provided herein. In someembodiments, provided herein are methods of inhibiting kinase activityin a subject by administering into the subject an effective amount of acompound as provided herein, or a pharmaceutically acceptable formthereof. In some embodiments, the kinase activity is inhibited (e.g.,reduced) by more than about 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%,when contacted with a compound provided herein as compared to the kinaseactivity without such contact. In some embodiments, provided herein aremethods of inhibiting PI3 kinase activity in a subject (includingmammals such as humans) by contacting said subject with an amount of acompound as provided herein sufficient to inhibit or reduce the activityof the PI3 kinase in said subject.

In some embodiments, the kinase is a lipid kinase or a protein kinase.In some embodiments, the kinase is selected from a PI3 kinase includingdifferent isoforms, such as PI3 kinase α, PI3 kinase β, PI3 kinase γ,PI3 kinase δ; DNA-PK; mTOR; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEKreceptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3);Platelet derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1;Hck; Src; Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor(IR); and IGFR.

As used herein, a “PI3K-mediated disorder” refers to a disease orcondition involving aberrant PI3K-mediated signaling pathway. In oneembodiment, provided herein is a method of treating a PI3K mediateddisorder in a subject, the method comprising administering atherapeutically effective amount of a compound as provided herein, or apharmaceutically acceptable form thereof, or a pharmaceuticalcomposition as provided herein. In some embodiments, provided herein isa method of treating a PI3K-δ or PI3K-γ mediated disorder in a subject,the method comprising administering a therapeutically effective amountof a compound as provided herein, or a pharmaceutically acceptable formthereof, or a pharmaceutical composition as provided herein. In someembodiments, provided herein is a method for inhibiting at least one ofPI3K-δ and PI3K-γ, the method comprising contacting a cell expressingPI3K in vitro or in vivo with an effective amount of a compound orcomposition provided herein. PI3Ks have been associated with a widerange of conditions, including immunity, cancer and thrombosis (reviewedin Vanhaesebroeck, B. et al. (2010) Current Topics in Microbiology andImmunology, DOI 10.1007/82_(—)2010_(—)65). For example, Class I PI3Ks,particularly PI3K-γ and PI3K-δ isoforms, are highly expressed inleukocytes and have been associated with adaptive and innate immunity;thus, these PI3Ks are believed to be important mediators in inflammatorydisorders and hematologic malignancies (reviewed in Harris, S J et al.(2009) Curr Opin Investig Drugs 10(11):1151-62); Rommel C. et al. (2007)Nat Rev Immunol 7(3):191-201; Durand C A et al. (2009) J Immunol.183(9):5673-84; Dil N, Marshall A J. (2009) Mol Immunol. 46(10):1970-8;Al-Alwan M M et al. (2007) J Immunol. 178(4):2328-35; Zhang T T, et al.(2008) J Allergy Clin Immunol. 2008; 122(4):811-819.e2; Srinivasan L, etal. (2009) Cell 139(3):573-86).

PI3K-γ is a Class 1B PI3K that associates with the p101 and p84(p87PIKAP) adaptor proteins, and canonically signals through GPCRs.Non-cononical activation through tyrosine kinase receptors and RAS canoccur. Activated PI3K-γ leads to production of PIP3, which serves as adocking site for downstream effector proteins including AKT and BTK,bringing these enzymes to the cell membrane where they may be activated.A scaffolding role for PI3k-γ has been proposed and may contribute tothe activation of the RAS/MEK/ERK pathway. The interaction with the RASpathway explains activities attributed to kinase dead PI3K-γ in cells orin animals. PI3K-γ is essential for function of a variety of immunecells and pathways. Chemokine responses (including IL-8, fMLP, and C5a),leading to neutrophil or monocyte cell migration, is dependent on PI3K-γ(HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide3-Kinase γ in Inflammation,” Science 287:1049-1053 (2000); SASAKI etal., “Function of PI3Kγ in Thymocyte Development, T Cell Activation, andNeutrophil Migration,” Science 287:1040-1046 (2000); LI et al., “Rolesof PLC-β2 and -β3 and PI3Kγ in Chemoattractant-Mediated SignalTransduction,” Science 287:1046-1049 (2000)). The requirement forPI3K-γ-dependent neutrophil migration is demonstrated by failure ofarthritis development in the K/BXN serum transfer arthritis model inPI3K-γ knockout mice (Randis et al., Eur. J. Immunol., 2008, 38(5),1215-24). Similarly, the mice fail to develop cellular inflammation andairway hyper-responsiveness in the ovalbumin induced asthma model(Takeda et al., J. Allergy Clin. Immunol., 2009; 123, 805-12). PI3K-γdeficient mice also have defects in T-helper cell function. T-cellcytokine production and proliferation in response to activation isreduced, and T helper dependent viral clearance is defective (Sasaki etal., Science, 2000, 287, 1040-46). T cell dependent inflammatory diseasemodels including EAE also do not develop in PI3K-γ deficient mice, andboth the T-cell activation defect and cellular migration defects maycontribute to efficacy in this model (Comerfold, PLOS One, 2012, 7,e45095). The imiquimod psoriasis model has also been used to demonstratethe importance of PI3K-γ in the inflammatory response. Using PI3K-γdeficient mice in this model, the accumulation of γδ T cells in the skinis blocked, as well as dendritic cell maturation and migration (ROLLERet al., “Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3KγReduces IL-17 and Ameliorates Imiquimod-Induced Psoriasis-likeDermatitis,” J. Immunol. 189:4612-4620 (2012)). The role of PI3K-γ incellular trafficking can also be demonstrated in oncology models wheretumor inflammation is important for growth and metastasis of cancers. Inthe Lewis Lung Carcinoma model, monocyte activation, migration, anddifferentiation in tumors are defective. This defect results in areduction in tumor growth and extended survival in PI3K-γ deficient mice(Schmid et al., Cancer Cell, 2011, 19, 715-27) or upon treatment withinhibitors that target PI3K-γ. In pancreatic cancer, PI3K-γ can beinappropriately expressed, and in this solid tumor cancer or otherswhere PI3K-γ plays a functional role, inhibition of PI3K-γ can bebeneficial Inhibition of PI3K-γ shows promise for the treatment ofhematologic malignancies. In a T-ALL model employing a T cell directedknockout of P-Ten, PI3K-δ and PI3K-γ are both essential for theappropriate development of disease, as shown with genetic deletion ofboth genes (Subramaniam et al. Cancer Cell 21, 459-472, 2012). Inaddition, in this TALL model, treatment with a small molecule inhibitorof both kinases leads to extended survival of these mice. In CLL,chemokine networks support a pseudo-follicular microenvironment thatincludes Nurse like cells, stromal cells and T-helper cells. The rolesof PI3K-γ in the normal chemokine signaling and T cell biology suggestthe value of inhibiting this target in CLL (BURGER, “Inhibiting B-CellReceptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr.Mematol. Malig. Rep. 7:26-33 (2012)). Accordingly, PI3K-γ inhibitors aretherapeutically interesting for diseases of the immune system where celltrafficking and T cell or myeloid cell function is important. Inoncology, solid tumors that are dependent on tumor inflammation, ortumors with high levels of PI3K-γ expression, may be targeted. Forhematological cancers a special role for PI3K-γ and PI3K-δ isoforms inTALL and potentially in CLL suggests targeting these PI3Ks in thesediseases.

Without being limited by a particular theory, PI3K-γ has been shown toplay roles in inflammation, arthritis, asthma, allergy, multiplesclerosis (MS), and cancer, among others (e.g., Ruckle et al., NatureRev., Drug Discovery, 2006, 5, 903-18; Schmid et al., “Myeloid cells intumor inflammation,” Vascular Cell, 2012, doi:10.1186/2045-824X-4-14).For example, PI3K-γ functions in multiple signaling pathways involved inleukocyte activation and migration. PI3K-γ has been shown to drivepriming and survival of autoreactive CD4⁺ T cells during experimentalautoimmune encephalomyelitis (EAE), a model for MS. When administeredfrom onset of EAE, a PI3K-γ inhibitor has been shown to cause inhibitionand reversal of clinical disease, and reduction of demyelination andcellular pathology in the CNS (Comerford et al., PLOS One, 2012, 7,e45095). PI3K-γ also regulates thymocyte development, T cell activation,neutrophil migration, and the oxidative burst (Sasaki et al., Science,2000, 287, 1040-46). In addition, it is shown that allergic airwayhyper-responsiveness, inflammation, and remodeling do not develop inPI3K-γ deficient mice (Takeda et al., J. Allergy Clin. Immunol., 2009;123, 805-12). PI3K-γ is shown to be required for chemoattractant-inducedproduction of phosphatidylinositol 3,4,5-trisphosphate and has animportant role in chemoattractant-induced superoxide production andchemotaxis in mouse neutrophils and in production of T cell-independentantigen-specific antibodies composed of the immunoglobulin light chain(Li et al., Science, 2000, 287, 1046-49). PI3K-γ is reported to be acrucial signaling molecule required for macrophage accumulation ininflammation (Hirsch et al., Science, 2000, 287, 1049-53). In cancers,pharmacological or genetic blockade of p110γ suppresses inflammation,growth, and metastasis of implanted and spontaneous tumors, suggestingthat PI3K-γ can be an important therapeutic target in oncology (Schmidet al., Cancer Cell, 2011, 19, 715-27). For example, it is shown thatPI3K-γ has a tumor-specific high accumulation in pancreatic ductaladenocarcinoma (PDAC) in human, signifying a role of PI3K-γ inpancreatic cancer (Edling et al., Human Cancer Biology, 2010, 16(2),4928-37).

PI3K-δ has roles in impairments of B-cell signaling and development,antibody production, T-cell function, Th1 and Th2 differentiation, andmast and basophil degranulation. Without being limited by a particulartheory, PI3K-γ has roles in T-cell function, neutrophil and macrophagerecruitment, macrophage activation, neutrophil oxidative burst, anddendritic cell migration Inhibition of PI3K-δ and/or PI3K-γ isoforms canresult in efficacy against inflammation and cancer, e.g., in arthritis,asthma, multiple sclerosis (MS), and tumor models. For example,deficiency in PI3K-δ and/or PI3K-γ can result in efficacy in K/B×Narthritis model (Kyburz et al., Springer Semin. Immunopathology, 2003,25, 79-90) or K/B×N serum transfer model of arthritis (Randis et al.,Eur. J. Immunol., 2008, 38(5), 1215-24), where it is shown thatrecognition of the immune complexes depends on both PI3K-δ and PI3K-γ,whereas cell migration is dependent on PI3K-γ. Deficiency in PI3K-δ orPI3K-γ can also result in efficacy in murine ovalbumin (OVA) inducedallergic asthma model (Lee et al., FASEB J., 2006, 20, 455-65; Takeda etal., J. Allergy Clin. Immunol., 2009; 123, 805-12), where it is shownthat inhibition of either PI3K-δ or PI3K-γ inhibits ovalbumin inducedlung infiltration and improves airway responsiveness. Deficiency inPI3K-δ or PI3K-γ can also result in efficacy in murine experimentalautoimmune encephalomyelitis (model for MS), where it is shown thatPI3K-γ deletion may provide better efficacy as compared to PI3K-δdeletion (Haylock-Jacob et al., J. Autoimmunity, 2011, 36, 278-87;Comerford et al., PLOS One, 2012, 7, e45095), including reduction inT-cell receptor induced CD4⁺ T cell activation, leukocyte infiltrationand Th1/Th17 responses, and dendritic cell migration (Comerfold, PLOSOne, 2012, 7, e45095). Furthermore, inhibition of PI3K-γ can also resultin decreased tumor inflammation and growth (e.g., Lewis lung carcinomamodel, Schmid et al., Cancer Cell, 2011, 19(6), 715-27). PI3K-γ deletioncombined with PI3K-δ deletion results in increased survival in T-cellacute lymphoblastic leukemia (T-ALL) (Subramaniam et al., Cancer Cell,2012, 21, 459-72). Inhibitors of both PI3K-δ and PI3K-γ are also shownto be efficacious in PTEN-deleted T-ALL cell line (MOLT-4). In theabsence of PTEN phosphatase tumor suppressor function, PI3K-δ or PI3K-γalone can support the development of leukemia, whereas inactivation ofboth isoforms suppresses tumor formation. Thus, inhibitors of PI3K-δand/or PI3K-γ can be useful in treating inflammation, such as arthritis,allergic asthma, and MS; and in treating cancer, for example, due toeffects such as reductions in solid tumor associated inflammation,angiogenesis and tumor progression.

The importance of PI3K-δ in the development and function of B-cells issupported from inhibitor studies and genetic models. PI3K-δ is animportant mediator of B-cell receptor (BCR) signaling, and is upstreamof AKT, calcium flux, PLCγ, MAP kinase, P70S6k, and FOXO3a activation.PI3K-δ is also important in IL4R, S1P, and CXCR5 signaling, and has beenshown to modulate responses to toll-like receptors 4 and 9 Inhibitors ofPI3K-δ have shown the importance of PI3K-δ in B-cell development(Marginal zone and B1 cells), B-cell activation, chemotaxis, migrationand homing to lymphoid tissue, and in the control of immunoglobulinclass switching leading to the production of IgE. Clayton E et al.(2002) J Exp Med. 196(6):753-63; Bilancio A, et al. (2006) Blood107(2):642-50; Okkenhaug K. et al. (2002) Science 297(5583):1031-4;Al-Alwan M M et al. (2007) J Immunol. 178(4):2328-35; Zhang T T, et al.(2008) J Allergy Clin Immunol. 2008; 122(4):811-819.e2; Srinivasan L, etal. (2009) Cell 139(3):573-86).

In T-cells, PI3K-δ has been demonstrated to have a role in T-cellreceptor and cytokine signaling, and is upstream of AKT, PLCγ, andGSK3b. In PI3K-δ deletion or kinase-dead knock-in mice, or in inhibitorstudies, T-cell defects including proliferation, activation, anddifferentiation have been observed, leading to reduced T helper cell 2(TH2) response, memory T-cell specific defects (DTH reduction), defectsin antigen dependent cellular trafficking, and defects inchemotaxis/migration to chemokines (e.g., S1P, CCR7, CD62L). (Garcon F.et al. (2008) Blood 111(3):1464-71; Okkenhaug K et al. (2006). JImmunol. 177(8):5122-8; Soond D R, et al. (2010) Blood 115(11):2203-13;Reif K, (2004). J Immunol. 2004; 173(4):2236-40; Ji H. et al. (2007)Blood 110(8):2940-7; Webb L M, et al. (2005) J Immunol. 175(5):2783-7;Liu D, et al. (2010) J Immunol. 184(6):3098-105; Haylock-Jacobs S, etal. (2011) J Autoimmun. 2011; 36(3-4):278-87; Jarmin S J, et al. (2008)J Clin Invest. 118(3):1154-64).

Numerous publications support roles of PI3K-δ and PI3K-γ in thedifferentiation, maintenance, and activation of immune and malignantcells, as described in more detail herein.

PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocyteswhere they have distinct and non-overlapping roles in immune celldevelopment and function. See, e.g., PURI and GOLD, “Selectiveinhibitors of phosphoinositide 3-kinase delta: modulators of B-cellfunction with potential for treating autoimmune inflammatory disease andB-cell malignancies,” Front. Immunol. 3:256 (2012); BUITENHUIS et al.,“The role of the PI3k-PKB signaling module in regulation ofhematopoiesis,” Cell Cycle 8(4):560-566 (2009); HOELLENRIEGEL andBURGER, “Phosphoinositide 3′-kinase delta: turning off BCR signaling inChronic Lymphocytic Leukemia,” Oncotarget 2(10):737-738 (2011); HIRSCHet al., “Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γin Inflammation,” Science 287:1049-1053 (2000); LI et al., “Roles ofPLC-β2 and β3 and PI3Kγ in Chemoattractant-Mediated SignalTransduction,” Science 287:1046-1049 (2000); SASAKI et al., “Function ofPI3Ky in Thymocyte Development, T Cell Activation, and NeutrophilMigration,” Science 287:1040-1046 (2000); CUSHING et al., “PI3Kδ andPI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med.Chem. 55:8559-8581 (2012); MAXWELL et al., “Attenuation ofphosphoinositide 3-kinase δ signaling restrains autoimmune disease,” J.Autoimmun. 38:381-391 (2012); HAYLOCK-JACOBS et al., “PI3Kδ drives thepathogenesis of experimental autoimmune encephalomyelitis by inhibitingeffector T cell apoptosis and promoting Th17 differentiation,” J.Autoimmun. 36:278-287 (2011); SOOND et al., “PI3K p110δ regulates T-cellcytokine production during primary and secondary immune responses inmice and humans,” Blood 115(11):2203-2213 (2010); ROLLER et al.,“Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ ReducesIL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis,” J.Immunol. 189:4612-4620 (2012); CAMPS et al., “Blockade of PI3Kγsuppresses joint inflammation and damage in mouse models of rheumatoidarthritis,” Nat. Med. 11(9):936-943 (2005). As key enzymes in leukocytesignaling, PI3K-δ and PI3K-γ facilitate normal B-cell, T-cell andmyeloid cell functions including differentiation, activation, andmigration. See, e.g., HOELLENRIEGEL and BURGER, “Phosphoinositide3′-kinase delta: turning off BCR signaling in Chronic LymphocyticLeukemia,” Oncotarget 2(10):737-738 (2011); CUSHING et al., “PI3Kδ andPI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med.Chem. 55:8559-8581 (2012). PI3K-δ or PI3K-γ activity is critical forpreclinical models of autoimmune and inflammatory diseases. See, e.g.,HIRSCH et al., “Central Role for G Protein-Coupled Phosphoinositide3-Kinase γ in Inflammation,” Science 287:1049-1053 (2000); LI et al.,“Roles of PLC-β2 and -β3 and PI3Kγ in Chemoattractant-Mediated SignalTransduction,” Science 287:1046-1049 (2000); SASAKI et al., “Function ofPI3Kγ in Thymocyte Development, T Cell Activation, and NeutrophilMigration,” Science 287:1040-1046 (2000); CUSHING et al., “PI3Kδ andPI3Kγ as Targets for Autoimmune and Inflammatory Diseases,” J. Med.Chem. 55:8559-8581 (2012); MAXWELL et al., “Attenuation ofphosphoinositide 3-kinase δ signaling restrains autoimmune disease,” J.Autoimmun. 38:381-391 (2012); HAYLOCK-JACOBS et al., “PI3Kδ drives thepathogenesis of experimental autoimmune encephalomyelitis by inhibitingeffector T cell apoptosis and promoting Th17 differentiation,” J.Autoimmun. 36:278-287 (2011); SOOND et al., “PI3K p110δ regulates T-cellcytokine production during primary and secondary immune responses inmice and humans,” Blood 115(11):2203-2213 (2010); ROLLER et al.,“Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ ReducesIL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis,” J.Immunol. 189:4612-4620 (2012); CAMPS et al., “Blockade of PI3Kγsuppresses joint inflammation and damage in mouse models of rheumatoidarthritis,” Nat. Med. 11(9):936-943 (2005). Given the key role forPI3K-δ and PI3K-γ in immune function, inhibitors of the PI3K-δ and/or γhave therapeutic potential in immune-related inflammatory or neoplasticdiseases.

PI3K-δ and PI3K-γ are central to the growth and survival of B- andT-cell malignancies and inhibition of these isoforms may effectivelylimit these diseases. See, e.g., SUBRAMANIAM et al., “TargetingNonclassical Oncogenes for Therapy in T-ALL,” Cancer Cell 21:459-472(2012); LANNUTTI et al., “CAL-101 a p110δ selectivephosphatidylinositol-3-kinase inhibitor for the treatment of B-cellmalignancies, inhibits PI3K signaling and cellular viability,” Blood117(2):591-594 (2011). PI3K-δ and PI3K-γ support the growth and survivalof certain B-cell malignancies by mediating intracellular BCR signalingand interactions between the tumor cells and their microenvironment.See, e.g., PURI and GOLD, “Selective inhibitors of phosphoinositide3-kinase delta: modulators of B-cell function with potential fortreating autoimmune inflammatory disease and B-cell malignancies,”Front. Immunol. 3:256 (2012); HOELLENRIEGEL et al., “Thephosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cellreceptor signaling and chemokine networks in chronic lymphocyticleuckemia,” Blood 118(13):3603-3612 (2011); BURGER, “Inhibiting B-CellReceptor Signaling Pathways in Chronic Lymphocytic Leukemia,” Curr.Mematol. Malig. Rep. 7:26-33 (2012). Increased BCR signaling is acentral pathologic mechanism of B-cell malignancies and PI3K activationis a direct consequence of BCR pathway activation. See, e.g., BURGER,“Inhibiting B-Cell Receptor Signaling Pathways in Chronic LymphocyticLeukemia,” Curr. Mematol. Malig. Rep. 7:26-33 (2012); HERISHANU et al.,“The lymph node microenvironment promotes B-cell receptor signaling,NF-κB activation, and tumor proliferation in chronic lymphocyticleukemia,” Blood 117(2):563-574 (2011); DAVIS et al., “Chronic activeB-cell-receptor signaling in diffuse large B-cell lymphoma,” Nature463:88-92 (2010); PIGHI et al., “Phospho-proteomic analysis of mantlecell lymphoma cells suggests a pro-survival role of B-cell receptorsignaling,” Cell Oncol. (Dordr) 34(2):141-153 (2011); RIZZATTI et al.,“Gene expression profiling of mantle cell lymphoma cells revealsaberrant expression of genes from the PI3K-AKT, WNT and TGFβ signalingpathways,” Brit. J. Haematol. 130:516-526 (2005); MARTINEZ et al., “TheMolecular Signature of Mantle Cell Lymphoma Reveals Multiple SignalsFavoring Cell Survival,” Cancer Res. 63:8226-8232 (2003). Interactionsbetween malignant B-cells and supporting cells (eg, stromal cells,nurse-like cells) in the tumor microenvironment are important for tumorcell survival, proliferation, homing, and tissue retention. See, e.g.,BURGER, “Inhibiting B-Cell Receptor Signaling Pathways in ChronicLymphocytic Leukemia,” Curr. Mematol. Malig. Rep. 7:26-33 (2012);HERISHANU et al., “The lymph node microenvironment promotes B-cellreceptor signaling, NF-κB activation, and tumor proliferation in chroniclymphocytic leukemia,” Blood 117(2):563-574 (2011); KURTOVA et al.,“Diverse marrow stromal cells protect CLL cells from spontaneous anddrig-induced apoptosis: development of a reliable and reproduciblesystem to assess stromal cell adhesion-mediated drug resistance,” Blood114(20): 4441-4450 (2009); BURGER et al., “High-level expression of theT-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cellsin nurselike cell cocultures and after BCR stimulation,” Blood 113(13)3050-3058 (2009); QUIROGA et al., “B-cell antigen receptor signalingenhances chronic lymphocytic leukemia cell migration and survival:specific targeting with a novel spleen tyrosine kinase inhibitor, R406,”Blood 114(5):1029-1037 (2009) Inhibiting PI3K-δ,γ with an inhibitor incertain malignant B-cells can block the BCR-mediated intracellularsurvival signaling as well as key interactions with theirmicroenvironment that are critical for their growth.

PI3K-δ and PI3K-γ also play a direct role in the survival andproliferation of certain T-cell malignancies. See, e.g., SUBRAMANIAM etal., “Targeting Nonclassical Oncogenes for Therapy in T-ALL,” CancerCell 21:459-472 (2012). Aberrant PI3K-δ and PI3K-γ activity provides thesignals necessary for the development and growth of certain T-cellmalignancies. While BTK is expressed in B-cells, it is not expressed inT-cells, and therefore BTK is not a viable target for the treatment ofT-cell malignancies. See, e.g., NISITANI et al., “Posttranscriptionalregulation of Bruton's tyrosine kinase expression in antigenreceptor-stimulated splenic B cells,” PNAS 97(6):2737-2742 (2000); DEWEERS et al., “The Bruton's tyrosine kinase gene is expressed throughoutB cell differentiation, from early precursor B cell stages precedingimmunoglobulin gene rearrangement up to mature B cell stages,” Eur. J.Immunol. 23:3109-3114 (1993); SMITH et al., “Expression of Bruton'sAgammaglobulinemia Tyrosine Kinase Gene, BTK, Is SelectivelyDown-Regulated in T Lymphocytes and Plasma Cells,” J. Immunol.152:557-565 (1994). PI3K-δ and/or γ inhibitors may have uniquetherapeutic potential in T-cell malignancies.

In neutrophils, PI3K-δ, along with PI3K-γ, contribute to the responsesto immune complexes, FCγRII signaling, including migration andneutrophil respiratory burst. Human neutrophils undergo rapid inductionof PIP3 in response to formyl peptide receptor (FMLP) or complementcomponent C5a (C5a) in a PI3K-γ dependent manner, followed by a longerPIP3 production period that is PI3K-δ dependent, and is essential forrespiratory burst. The response to immune complexes is contributed byPI3K-δ, PI3K-γ, and PI3K-β, and is an important mediator of tissuedamage in models of autoimmune disease (Randis T M et al. (2008) Eur JImmunol. 38(5):1215-24; Pinho V, (2007) J Immunol. 179(11):7891-8; SadhuC. et al. (2003) J Immunol. 170(5):2647-54; Condliffe A M et al. (2005)Blood 106(4):1432-40). It has been reported that in certain autoimmunediseases, preferential activation of PI3K-β may be involved (Kulkarni etal., Immunology (2011) 4(168) ra23: 1-11). It was also reported thatPI3K-β-deficient mice were highly protected in an FcγR-dependent modelof autoantibody-induced skin blistering and partially protected in anFcγR-dependent model of inflammatory arthritis, whereas combineddeficiency of PI3K-β and PI3K-δ resulted in near complete protection ininflammatory arthritis (Id.).

In macrophages collected from patients with chronic obstructivepulmonary disease (COPD), glucocorticoid responsiveness can be restoredby treatment of the cells with inhibitors of PI3K-δ. Macrophages alsorely on PI3K-δ and PI3K-γ for responses to immune complexes through thearthus reaction (FCγR and C5a signaling) (Randis T M, et al. (2008) EurJ Immunol. 38(5):1215-24; Marwick J A et al. (2009) Am J Respir CritCare Med. 179(7):542-8; Konrad S, et al. (2008) J Biol Chem.283(48):33296-303).

In mast cells, stem cell factor—(SCF) and IL3-dependent proliferation,differentiation and function are PI3K-δ dependent, as is chemotaxis. Theallergen/IgE crosslinking of FCγR1 resulting in cytokine release anddegranulation of the mast cells is severely inhibited by treatment withPI3K-δ inhibitors, suggesting a role for PI3K-δ in allergic disease (AliK et al. (2004) Nature 431(7011):1007-11; Lee K S, et al. (2006) FASEBJ. 20(3):455-65; Kim M S, et al. (2008) Trends Immunol. 29(10):493-501).

Natural killer (NK) cells are dependent on both PI3K-δ and PI3K-γ forefficient migration towards chemokines including CXCL10, CCL3, S1P andCXCL12, or in response to LPS in the peritoneum (Guo H, et al. (2008) JExp Med. 205(10):2419-35; Tassi I, et al. (2007) Immunity 27(2):214-27;Saudemont A, (2009) Proc Natl Acad Sci USA. 106(14):5795-800; Kim N, etal. (2007) Blood 110(9):3202-8).

The roles of PI3K-δ and PI3K-γ in the differentiation, maintenance, andactivation of immune cells support a role for these enzymes ininflammatory disorders ranging from autoimmune diseases (e.g.,rheumatoid arthritis, multiple sclerosis) to allergic inflammatorydisorders, such as asthma, and inflammatory respiratory disease, such asCOPD. Extensive evidence is available in experimental animal models, orcan be evaluated using art-recognized animal models. In an embodiment,described herein is a method of treating inflammatory disorders rangingfrom autoimmune diseases (e.g., rheumatoid arthritis, multiplesclerosis) to allergic inflammatory disorders, such as asthma and COPDusing a compound described herein.

For example, inhibitors of PI3K-δ and/or -γ have been shown to haveanti-inflammatory activity in several autoimmune animal models forrheumatoid arthritis (Williams, O. et al. (2010) Chem Biol,17(2):123-34; WO 2009/088986; WO2009/088880; WO 2011/008302; eachincorporated herein by reference). PI3K-δ is expressed in the RAsynovial tissue (especially in the synovial lining which containsfibroblast-like synoviocytes (FLS), and selective PI3K-δ inhibitors havebeen shown to be effective in inhibiting synoviocyte growth and survival(Bartok et al. (2010) Arthritis Rheum 62 Suppl 10:362). Several PI3K-δand -γ inhibitors have been shown to ameliorate arthritic symptoms(e.g., swelling of joints, reduction of serum-induced collagen levels,reduction of joint pathology and/or inflammation), in art-recognizedmodels for RA, such as collagen-induced arthritis and adjuvant inducedarthritis (WO 2009/088986; WO2009/088880; WO 2011/008302; eachincorporated herein by reference).

The role of PI3K-δ has also been shown in models of T-cell dependentresponse, including the DTH model. In the murine experimental autoimmuneencephalomyelitis (EAE) model of multiple sclerosis, the PI3K-γ/δ-doublemutant mice are resistant. PI3K-δ inhibitors have also been shown toblock EAE disease induction and development of TH-17 cells both in vitroand in vivo (Haylock-Jacobs, S. et al. (2011) J. Autoimmunity36(3-4):278-87).

Systemic lupus erythematosus (SLE) is a complex disease that atdifferent stages requires memory T-cells, B-cell polyclonal expansionand differentiation into plasma cells, and the innate immune response toendogenous damage associated molecular pattern molecules (DAMPS), andthe inflammatory responses to immune complexes through the complementsystem as well as the F_(C) receptors. The role of PI3K-δ and PI3K-γtogether in these pathways and cell types suggest that blockade with aninhibitor would be effective in these diseases. A role for PI3K in lupusis also predicted by two genetic models of lupus. The deletion ofphosphatase and tensin homolog (PTEN) leads to a lupus-like phenotype,as does a transgenic activation of Class 1A PI3Ks, which includesPI3K-δ. The deletion of PI3K-γ in the transgenically activated class 1Alupus model is protective, and treatment with a PI3K-γ selectiveinhibitor in the murine MLR/lpr model of lupus improves symptoms(Barber, D F et al. (2006) J. Immunol. 176(1): 589-93).

In allergic disease, PI3K-δ has been shown by genetic models and byinhibitor treatment to be essential for mast-cell activation in apassive cutaneous anaphalaxis assay (Ali K et al. (2008) J Immunol.180(4):2538-44; Ali K, (2004) Nature 431(7011):1007-11). In a pulmonarymeasure of response to immune complexes (Arthus reaction) a PI3K-δknockout is resistant, showing a defect in macrophage activation and C5aproduction. Knockout studies and studies with inhibitors for both PI3K-δand PI3K-γ support a role for both of these enzymes in the ovalbumininduced allergic airway inflammation and hyper-responsiveness model (LeeK S et al. (2006) FASEB J. 20(3):455-65). Reductions of infiltration ofeosinophils, neutrophils, and lymphocytes as well as TH2 cytokines (IL4,IL5, and IL13) were seen with both PI3K-δ specific and dual PI3K-δ andPI3K-γ inhibitors in the Ova induced asthma model (Lee K S et al. (2006)J Allergy Clin Immunol 118(2):403-9).

PI3K-δ and PI3K-γ inhibition can be used in treating COPD. In the smokedmouse model of COPD, the PI3K-δ knockout does not develop smoke inducedglucocorticoid resistance, while wild-type and PI3K-γ knockout mice do.An inhaled formulation of dual PI3K-δ and PI3K-γ inhibitor blockedinflammation in a LPS or smoke COPD models as measured by neutrophiliaand glucocorticoid resistance (Doukas J, et al. (2009) J Pharmacol ExpTher. 328(3):758-65).

Class I PI3Ks, particularly PI3K-δ and PI3K-γ isoforms, are alsoassociated with cancers (reviewed, e.g., in Vogt, P K et al. (2010) CurrTop Microbiol Immunol. 347:79-104; Fresno Vara, J A et al. (2004) CancerTreat Rev. 30(2):193-204; Zhao, L and Vogt, P K. (2008) Oncogene27(41):5486-96). Inhibitors of PI3K, e.g., PI3K-δ and/or PI3K-γ, havebeen shown to have anti-cancer activity (e.g., Courtney, K D et al.(2010) J Clin Oncol. 28(6):1075-1083); Markman, B et al. (2010) AnnOncol. 21(4):683-91; Kong, D and Yamori, T (2009) Curr Med Chem.16(22):2839-54; Jimeno, A et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3542); Flinn, I W et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3543); Shapiro, G et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3500); Wagner, A J et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3501); Vogt, P K et al. (2006) Virology 344(1):131-8; Ward, S etal. (2003) Chem Biol. 10(3):207-13; WO 2011/041399; US 2010/0029693; US2010/0305096; US 2010/0305084; each incorporated herein by reference).

In one embodiment, described herein is a method of treating cancer.Types of cancer that can be treated with an inhibitor of PI3K(particularly, PI3K-δ and/or PI3K-γ) include, e.g., leukemia, chroniclymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia(e.g., Salmena, L et al. (2008) Cell 133:403-414; Chapuis, N et al.(2010) Clin Cancer Res. 16(22):5424-35; Khwaja, A (2010) Curr TopMicrobiol Immunol. 347:169-88); lymphoma, e.g., non-Hodgkin's lymphoma(e.g., Salmena, L et al. (2008) Cell 133:403-414); lung cancer, e.g.,non-small cell lung cancer, small cell lung cancer (e.g., Herrera, V Aet al. (2011) Anticancer Res. 31(3):849-54); melanoma (e.g., Haluska, Fet al. (2007) Semin Oncol. 34(6):546-54); prostate cancer (e.g., Sarker,D et al. (2009) Clin Cancer Res. 15(15):4799-805); glioblastoma (e.g.,Chen, J S et al. (2008) Mol Cancer Ther. 7:841-850); endometrial cancer(e.g., Bansal, N et al. (2009) Cancer Control. 16(1):8-13); pancreaticcancer (e.g., Furukawa, T (2008) J Gastroenterol. 43(12):905-11); renalcell carcinoma (e.g., Porta, C and Figlin, R A (2009) J Urol.182(6):2569-77); colorectal cancer (e.g., Saif, M W and Chu, E (2010)Cancer J. 16(3):196-201); breast cancer (e.g., Torbett, N E et al.(2008) Biochem J. 415:97-100); thyroid cancer (e.g., Brzezianska, E andPastuszak-Lewandoska, D (2011) Front Biosci. 16:422-39); and ovariancancer (e.g., Mazzoletti, M and Broggini, M (2010) Curr Med Chem.17(36):4433-47).

Numerous publications support a role of PI3K-δ and PI3K-γ in treatinghematological cancers. PI3K-δ and PI3K-γ are highly expressed in theheme compartment, and some solid tumors, including prostate, breast andglioblastomas (Chen J. S. et al. (2008) Mol Cancer Ther. 7(4):841-50;Ikeda H. et al. (2010) Blood 116(9):1460-8).

In hematological cancers including acute myeloid leukemia (AML),multiple myeloma (MM), and chronic lymphocytic leukemia (CLL),overexpression and constitutive activation of PI3K-δ supports the modelthat PI3K-δ inhibition would be therapeutic Billottet C, et al. (2006)Oncogene 25(50):6648-59; Billottet C, et al. (2009) Cancer Res.69(3):1027-36; Meadows, S A, 52^(nd) Annual ASH Meeting and Exposition;2010 Dec. 4-7; Orlando, Fla.; Ikeda H, et al. (2010) Blood116(9):1460-8; Herman S E et al. (2010) Blood 116(12):2078-88; Herman SE et al. (2011). Blood 117(16):4323-7.

In one embodiment, described herein is a method of treatinghematological cancers including, but not limited to acute myeloidleukemia (AML), multiple myeloma (MM), and chronic lymphocytic leukemia(CLL).

A PI3K-δ inhibitor (CAL-101) has been evaluated in a phase 1 trial inpatients with haematological malignancies, and showed activity in CLL inpatients with poor prognostic characteristics. In CLL, inhibition ofPI3K-δ not only affects tumor cells directly, but it also affects theability of the tumor cells to interact with their microenvironment. Thismicroenvironment includes contact with and factors from stromal cells,T-cells, nurse like cells, as well as other tumor cells. CAL-101suppresses the expression of stromal and T-cell derived factorsincluding CCL3, CCL4, and CXCL13, as well as the CLL tumor cells'ability to respond to these factors. CAL-101 treatment in CLL patientsinduces rapid lymph node reduction and redistribution of lymphocytesinto the circulation, and affects tonic survival signals through theBCR, leading to reduced cell viability, and an increase in apoptosis.Single agent CAL-101 treatment was also active in mantle cell lymphomaand refractory non Hodgkin's lymphoma (Furman, R R, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.;Hoellenriegel, J, et al. 52^(nd) Annual ASH Meeting and Exposition; 2010Dec. 4-7; Orlando, Fla.; Webb, H K, et al. 52^(nd) Annual ASH Meetingand Exposition; 2010 Dec. 4-7; Orlando, Fla.; Meadows, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.; Kahl,B, et al. 52^(nd) Annual ASH Meeting and Exposition; 2010 Dec. 4-7;Orlando, Fla.; Lannutti B J, et al. (2011) Blood 117(2):591-4).

PI3K-δ inhibitors have shown activity against PI3K-δ positive gliomas invitro (Kashishian A, et al. Poster presented at: The AmericanAssociation of Cancer Research 102^(nd) Annual Meeting; 2011 Apr. 2-6;Orlando, Fla.). PI3K-δ is the PI3K isoform that is most commonlyactivated in tumors where the PTEN tumor suppressor is mutated (Ward S,et al. (2003) Chem Biol. 10(3):207-13). In this subset of tumors,treatment with the PI3K-δ inhibitor either alone or in combination witha cytotoxic agent can be effective.

Another mechanism for PI3K-δ inhibitors to have an effect in solidtumors involves the tumor cells' interaction with theirmicro-environment. PI3K-δ, PI3K-γ, and PI3K-β are expressed in theimmune cells that infiltrate tumors, including tumor infiltratinglymphocytes, macrophages, and neutrophils. PI3K-δ inhibitors can modifythe function of these tumor-associated immune cells and how they respondto signals from the stroma, the tumor, and each other, and in this wayaffect tumor cells and metastasis (Hoellenriegel, J, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.).

PI3K-δ is also expressed in endothelial cells. It has been shown thattumors in mice treated with PI3K-δ selective inhibitors are killed morereadily by radiation therapy. In this same study, capillary networkformation is impaired by the PI3K inhibitor, and it is postulated thatthis defect contributes to the greater killing with radiation. PI3K-δinhibitors can affect the way in which tumors interact with theirmicroenvironment, including stromal cells, immune cells, and endothelialcells and be therapeutic either on its own or in conjunction withanother therapy (Meadows, S A, et al. Paper presented at: 52^(nd) AnnualASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.; Geng L, et al.(2004) Cancer Res. 64(14):4893-9).

In one embodiment, provided herein is a method of treating or preventinga cancer or disease, such as hematologic malignancy, or a specific typeor sub-type of cancer or disease, such as a specific type or sub-type ofhematologic malignancy, with a PI3K-γ selective inhibitor, wherein theadverse effects associated with administration of inhibitors for otherisoform(s) of PI3K (e.g., PI3K-α and/or PI3K-β) are reduced. In oneembodiment, provided herein is a method of treating or preventing acancer or disease, such as hematologic malignancy, or a specific type orsub-type of cancer or disease, such as a specific type or sub-type ofhematologic malignancy, with a PI3K-γ selective inhibitor, at a lower(e.g., by about 10%, by about 20%, by about 30%, by about 40%, by about50%, by about 60%, by about 70%, or by about 80%) dose as compared totreatment with a PI3K-γ non-selective or less selective inhibitor (e.g.,a PI3Kpan inhibitors, e.g., inhibiting PI3K-α, β, δ, and γ).

The role of PI3K-γ pathway in promoting myeloid cell trafficking totumors and the role of blockade of p100γ in suppression of tumorinflammation and growth in breast cancer, pancreatic cancer, and lungcancer are reported, for example, in Schmid et al. (2011) Cancer Cell19, 715-727, the entirety of which is incorporated herein by reference.In one embodiment, provided herein is a method of treating or preventingpancreatic cancer with a PI3K inhibitor. In another embodiment, providedherein is a method of treating or preventing breast cancer with a PI3Kinhibitor. In yet another embodiment, provided herein is a method oftreating or preventing lung cancer with a PI3K inhibitor. In oneembodiment, the PI3K inhibitor is a PI3K-γ inhibitor, selective ornon-selective over one or more other PI3K isoform(s). In one embodiment,the PI3K inhibitor is a PI3K-γ selective inhibitor.

In certain embodiments, provided herein is a method of treating adisorder or disease provided herein, comprising administering a compoundprovided herein, e.g., a PI3K γ selective inhibitor, a PI3K δ selectiveinhibitor, or a PI3K γ/δ dual inhibitor. Without being limited by aparticular theory, in some embodiments, selectively inhibiting PI3K-γisoform can provide a treatment regimen where adverse effects associatedwith administration of a non-selective PI3K inhibitor are minimized orreduced. Without being limited by a particular theory, in someembodiments, selectively inhibiting PI3K-δ isoform can provide atreatment regimen where adverse effects associated with administrationof a non-selective PI3K inhibitor are minimized or reduced. Withoutbeing limited by a particular theory, in some embodiments, selectivelyinhibiting PI3K-δ and γ isoform can provide a treatment regimen whereadverse effects associated with administration of a non-selective PI3Kinhibitor are minimized or reduced. Without being limited by aparticular theory, it is believed that the adverse effects can bereduced by avoiding the inhibition of other isoforms (e.g., α or β) ofPI3K.

In one embodiment, the adverse effect is hyperglycemia. In anotherembodiment, the adverse effect is rash. In another embodiment, theadverse effect is impaired male fertility that may result frominhibition of β isoform of PI3K (see, e.g., Ciraolo et al., MolecularBiology of the Cell, 21: 704-711 (2010)). In another embodiment, theadverse effect is testicular toxicity that may result from inhibition ofPI3K-β (see, e.g., Wisler et al., Amgen S O T, Abstract ID #2334(2012)). In another embodiment, the adverse effect is embryoniclethality (see, e.g., Bi et al., J Biol Chem, 274: 10963-10968 (1999)).In another embodiment, the adverse effect is defective plateletaggregation (see, e.g., Kulkarni et al., Science, 287: 1049-1053(2000)). In another embodiment, the adverse effect is functionallydefective neutrophil (id.).

In certain embodiments, the PI3K-γ inhibitor selectively modulatesphosphatidyl inositol-3 kinase (PI3 kinase) gamma isoform. In oneembodiment, the PI3K-γ inhibitor selectively inhibits the gamma isoformover the alpha, beta, or delta isoform. In one embodiment, the PI3K-γinhibitor selectively inhibits the gamma isoform over the alpha or betaisoform. In one embodiment, the PI3K-γ inhibitor selectively inhibitsthe gamma isoform over the alpha, beta, and delta isoforms. In oneembodiment, the PI3K-γ inhibitor selectively inhibits the gamma isoformover the alpha and beta isoforms. In one embodiment, the PI3K-γinhibitor selectively inhibits the gamma isoform over the alpha and betaisoforms, but not the delta isoform. By way of non-limiting example, theratio of selectivity can be greater than a factor of about 10, greaterthan a factor of about 50, greater than a factor of about 100, greaterthan a factor of about 200, greater than a factor of about 400, greaterthan a factor of about 600, greater than a factor of about 800, greaterthan a factor of about 1000, greater than a factor of about 1500,greater than a factor of about 2000, greater than a factor of about5000, greater than a factor of about 10,000, or greater than a factor ofabout 20,000, where selectivity can be measured by IC₅₀, among othermeans. In certain embodiments, the PI3 kinase gamma isoform IC₅₀activity of a compound as disclosed herein can be less than about 1000nM, less than about 100 nM, less than about 10 nM, or less than about 1nM. For example, a compound that selectively inhibits one isoform ofPI3K over another isoform of PI3K has an activity of at least 2× againsta first isoform relative to the compound's activity against the secondisoform (e.g., at least about 3×, 5×, 10×, 20×, 50×, 100×, 200×, 500×,or 1000×).

In other embodiments, inhibition of PI3K (such as PI3K-δ and/or PI3K-γ)can be used to treat a neuropsychiatric disorder, e.g., an autoimmunebrain disorder. Infectious and immune factors have been implicated inthe pathogenesis of several neuropsychiatric disorders, including, butnot limited to, Sydenham's chorea (SC) (Garvey, M. A. et al. (2005) J.Child Neurol. 20:424-429), Tourette's syndrome (TS), obsessivecompulsive disorder (OCD) (Asbahr, F. R. et al. (1998) Am. J. Psychiatry155:1122-1124), attention deficit/hyperactivity disorder (AD/HD)(Hirschtritt, M. E. et al. (2008) Child Neuropsychol. 1:1-16; Peterson,B. S. et al. (2000) Arch. Gen. Psychiatry 57:364-372), anorexia nervosa(Sokol, M. S. (2000) J. Child Adolesc. Psychopharmacol. 10:133-145;Sokol, M. S. et al. (2002) Am. J. Psychiatry 159:1430-1432), depression(Leslie, D. L. et al. (2008) J. Am. Acad. Child Adolesc. Psychiatry47:1166-1172), and autism spectrum disorders (ASD) (Hollander, E. et al.(1999) Am. J. Psychiatry 156:317-320; Margutti, P. et al. (2006) Curr.Neurovasc. Res. 3:149-157). A subset of childhood obsessive compulsivedisorders and tic disorders has been grouped as Pediatric AutoimmuneNeuropsychiatric Disorders Associated with Streptococci (PANDAS). PANDASdisorders provide an example of disorders where the onset andexacerbation of neuropsychiatric symptoms is preceded by a streptococcalinfection (Kurlan, R., Kaplan, E. L. (2004) Pediatrics 113:883-886;Garvey, M. A. et al. (1998) J. Clin. Neurol. 13:413-423). Many of thePANDAS disorders share a common mechanism of action resulting fromantibody responses against streptococcal associated epitopes, such asGlcNAc, which produces neurological effects (Kirvan. C. A. et al. (2006)J. Neuroimmunol. 179:173-179). Autoantibodies recognizing centralnervous system (CNS) epitopes are also found in sera of most PANDASsubjects (Yaddanapudi, K. et al. (2010) Mol. Psychiatry 15:712-726).Thus, several neuropsychiatric disorders have been associated withimmune and autoimmune components, making them suitable for therapiesthat include PI3K-δ and/or PI3K-γ inhibition.

In certain embodiments, a method of treating (e.g., reducing orameliorating one or more symptoms of) a neuropsychiatric disorder,(e.g., an autoimmune brain disorder), using a PI3K-δ and/or PI3K-γinhibitor is described, alone or in combination therapy. For example,one or more PI3K-δ and/or PI3K-γ inhibitors described herein can be usedalone or in combination with any suitable therapeutic agent and/ormodalities, e.g., dietary supplement, for treatment of neuropsychiatricdisorders. Exemplary neuropsychiatric disorders that can be treated withthe PI3K-δ and/or PI3K-γ inhibitors described herein include, but arenot limited to, PANDAS disorders, Sydenham's chorea, Tourette'ssyndrome, obsessive compulsive disorder, attention deficit/hyperactivitydisorder, anorexia nervosa, depression, and autism spectrum disorders.Pervasive Developmental Disorder (PDD) is an exemplary class of autismspectrum disorders that includes Autistic Disorder, Asperger's Disorder,Childhood Disintegrative Disorder (CDD), Rett's Disorder and PDD-NotOtherwise Specified (PDD-NOS). Animal models for evaluating the activityof the PI3K-δ and/or PI3K-γ inhibitor are known in the art. For example,a mouse model of PANDAS disorders is described in, e.g., Yaddanapudi, K.et al. (2010) supra; and Hoffman, K. I. et al. (2004) J. Neurosci.24:1780-1791.

In some embodiments, provided herein is a method for treating rheumatoidarthritis or asthma in a subject, or for reducing a rheumatoidarthritis-associated symptom or an asthma-associated symptom in asubject, comprising administering an effective amount of a PI3K-γinhibitor to a subject in need thereof, wherein one or more of theadverse effects associated with administration of inhibitors for one ormore other isoforms of PI3K are reduced. In one embodiment, the one ormore other isoforms of PI3K is PI3K-α, PI3K-β, and/or PI3K-δ. In oneembodiment, the one or more other isoforms of PI3K is PI3K-α and/orPI3K-β. In one embodiment, the method is for treating rheumatoidarthritis in a subject, or for reducing a rheumatoidarthritis-associated symptom in a subject. In another embodiment, themethod is for treating asthma in a subject, or for reducing anasthma-associated symptom in a subject.

In some embodiments, provided herein are methods of using a compoundprovided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, to treat diseaseconditions, including, but not limited to, diseases associated withmalfunctioning of one or more types of PI3 kinase. In one embodiment, adetailed description of conditions and disorders mediated by p110δkinase activity is set forth in Sadu et al., WO 01/81346, which isincorporated herein by reference in its entirety for all purposes.

In some embodiments, the disclosure relates to a method of treating ahyperproliferative disorder in a subject that comprises administering tosaid subject a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or a pharmaceuticalcomposition as provided herein. In some embodiments, said method relatesto the treatment of cancer such as acute myeloid leukemia, thymus,brain, lung, squamous cell, skin, eye, retinoblastoma, intraocularmelanoma, oral cavity and oropharyngeal, bladder, gastric, stomach,pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver,ovarian, prostate, colorectal, esophageal, testicular, gynecological,thyroid, CNS, PNS, AIDS-related (e.g., Lymphoma and Kaposi's Sarcoma) orviral-induced cancer. In some embodiments, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis), restenosis, or prostate(e.g., benign prostatic hypertrophy (BPH)).

Patients that can be treated with a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein, according to the methods as provided herein include, forexample, but not limited to, patients that have been diagnosed as havingpsoriasis; restenosis; atherosclerosis; BPH; breast cancer such as aductal carcinoma in duct tissue in a mammary gland, medullarycarcinomas, colloid carcinomas, tubular carcinomas, and inflammatorybreast cancer; ovarian cancer, including epithelial ovarian tumors suchas adenocarcinoma in the ovary and an adenocarcinoma that has migratedfrom the ovary into the abdominal cavity; uterine cancer; cervicalcancer such as adenocarcinoma in the cervix epithelial includingsquamous cell carcinoma and adenocarcinomas; prostate cancer, such as aprostate cancer selected from the following: an adenocarcinoma or anadenocarcinoma that has migrated to the bone; pancreatic cancer such asepitheliod carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct; bladder cancer such as a transitional cellcarcinoma in urinary bladder, urothelial carcinomas (transitional cellcarcinomas), tumors in the urothelial cells that line the bladder,squamous cell carcinomas, adenocarcinomas, and small cell cancers;leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, NK cellleukemia (e.g., blastic plasmacytoid dendritic cell neoplasm), acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),and myelodysplastic syndrome (MDS); bone cancer; lung cancer such asnon-small cell lung cancer (NSCLC), which is divided into squamous cellcarcinomas, adenocarcinomas, and large cell undifferentiated carcinomas,and small cell lung cancer; skin cancer such as basal cell carcinoma,melanoma, squamous cell carcinoma and actinic keratosis, which is a skincondition that sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; lymphoma suchas diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, NK celllymphoma (e.g., blastic plasmacytoid dendritic cell neoplasm), and smallnon-cleaved cell lymphoma; Kaposi's Sarcoma; viral-induced cancersincluding hepatitis B virus (HBV), hepatitis C virus (HCV), andhepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1) andadult T-cell leukemia/lymphoma; and human papilloma virus (HPV) andcervical cancer; central nervous system cancers (CNS) such as primarybrain tumor, which includes gliomas (astrocytoma, anaplasticastrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma,Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheralnervous system (PNS) cancers such as acoustic neuromas and malignantperipheral nerve sheath tumor (MPNST) including neurofibromas andschwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma,malignant meningioma, malignant mesothelioma, and malignant mixedMüllerian tumor; oral cavity and oropharyngeal cancer such as,hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, andoropharyngeal cancer; stomach cancer such as lymphomas, gastric stromaltumors, and carcinoid tumors; testicular cancer such as germ cell tumors(GCTs), which include seminomas and nonseminomas, and gonadal stromaltumors, which include Leydig cell tumors and Sertoli cell tumors; thymuscancer such as to thymomas, thymic carcinomas, Hodgkin disease,non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; andcolon cancer.

In one embodiment, provided herein is a method of treating aninflammation disorder, including autoimmune diseases in a subject. Themethod comprises administering to said subject a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein. Examples ofautoimmune diseases include but are not limited to acute disseminatedencephalomyelitis (ADEM), Addison's disease, antiphospholipid antibodysyndrome (APS), aplastic anemia, autoimmune hepatitis, autoimmune skindisease, coeliac disease, Crohn's disease, Diabetes mellitus (type 1),Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS),Hashimoto's disease, lupus erythematosus, multiple sclerosis, myastheniagravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord'sthyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis,psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu'sarteritis, temporal arteritis (also known as “giant cell arteritis”),warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopeciauniversalis (e.g., inflammatory alopecia), Chagas disease, chronicfatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa,interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma,ulcerative colitis, vitiligo, and vulvodynia. Other disorders includebone-resorption disorders and thrombosis.

Inflammation takes on many forms and includes, but is not limited to,acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse,disseminated, exudative, fibrinous, fibrosing, focal, granulomatous,hyperplastic, hypertrophic, interstitial, metastatic, necrotic,obliterative, parenchymatous, plastic, productive, proliferous,pseudomembranous, purulent, sclerosing, seroplastic, serous, simple,specific, subacute, suppurative, toxic, traumatic, and/or ulcerativeinflammation.

Exemplary inflammatory conditions include, but are not limited to,inflammation associated with acne, anemia (e.g., aplastic anemia,haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthritis, psoriaticarthritis, gout flare, gouty arthritis, reactive arthritis, rheumatoidarthritis and Reiter's arthritis), ankylosing spondylitis, amylosis,amyotrophic lateral sclerosis, autoimmune diseases, allergies orallergic reactions, atherosclerosis, bronchitis, bursitis, chronicprostatitis, conjunctivitis, Chagas disease, chronic obstructivepulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., typeI diabetes mellitus, type 2 diabetes mellitus), a skin condition (e.g.,psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis,Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasakidisease, glomerulonephritis, gingivitis, hypersensitivity, headaches(e.g., migraine headaches, tension headaches), ileus (e.g.,postoperative ileus and ileus during sepsis), idiopathicthrombocytopenic purpura, interstitial cystitis (painful bladdersyndrome), gastrointestinal disorder (e.g., selected from peptic ulcers,regional enteritis, diverticulitis, gastrointestinal bleeding,eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, orits synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn'sdisease, ulcerative colitis, collagenous colitis, lymphocytic colitis,ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminatecolitis) and inflammatory bowel syndrome (IBS)), lupus, multiplesclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephroticsyndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers,polymyositis, primary biliary cirrhosis, neuroinflammation associatedwith brain disorders (e.g., Parkinson's disease, Huntington's disease,and Alzheimer's disease), prostatitis, chronic inflammation associatedwith cranial radiation injury, pelvic inflammatory disease, polymyalgiarheumatic, reperfusion injury, regional enteritis, rheumatic fever,systemic lupus erythematosus, scleroderma, scierodoma, sarcoidosis,spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantationrejection, tendonitis, trauma or injury (e.g., frostbite, chemicalirritants, toxins, scarring, burns, physical injury), vasculitis,vitiligo and Wegener's granulomatosis. In certain embodiments, theinflammatory disorder is selected from arthritis (e.g., rheumatoidarthritis), inflammatory bowel disease, inflammatory bowel syndrome,asthma, psoriasis, endometriosis, interstitial cystitis andprostatistis. In certain embodiments, the inflammatory condition is anacute inflammatory condition (e.g., for example, inflammation resultingfrom infection). In certain embodiments, the inflammatory condition is achronic inflammatory condition (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds can also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia.

Immune disorders, such as auto-immune disorders, include, but are notlimited to, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, degenerative joint diseases suchas osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease,haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateralsclerosis, amylosis, acute painful shoulder, psoriatic, and juvenilearthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns,dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrointestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), relapsing polychondritis (e.g.,atrophic polychondritis and systemic polychondromalacia), and disordersameliorated by a gastroprokinetic agent (e.g., ileus, postoperativeileus and ileus during sepsis; gastroesophageal reflux disease (GORD, orits synonym GERD); eosinophilic esophagitis, gastroparesis such asdiabetic gastroparesis; food intolerances and food allergies and otherfunctional bowel disorders, such as non-ulcerative dyspepsia (NUD) andnon-cardiac chest pain (NCCP, including costo-chondritis)). In certainembodiments, a method of treating inflammatory or autoimmune diseases isprovided comprising administering to a subject (e.g., a mammal) atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein, that selectively inhibit PI3K-δ and/or PI3K-γ as compared to allother type I PI3 kinases. Such selective inhibition of PI3K-δ and/orPI3K-γ can be advantageous for treating any of the diseases orconditions described herein. For example, selective inhibition of PI3K-δand/or PI3K-γ can inhibit inflammatory responses associated withinflammatory diseases, autoimmune disease, or diseases related to anundesirable immune response including, but not limited to asthma,emphysema, allergy, dermatitis, rheumatoid arthritis, psoriasis, lupuserythematosus, anaphylaxsis, or graft versus host disease. Selectiveinhibition of PI3K-δ and/or PI3K-γ can further provide for a reductionin the inflammatory or undesirable immune response without a concomitantreduction in the ability to reduce a bacterial, viral, and/or fungalinfection. Selective inhibition of both PI3K-δ and PI3K-γ can beadvantageous for inhibiting the inflammatory response in the subject toa greater degree than that would be provided for by inhibitors thatselectively inhibit PI3K-δ or PI3K-γ alone. In one aspect, one or moreof the subject methods are effective in reducing antigen specificantibody production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold,7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold,750-fold, or about 1000-fold or more. In another aspect, one or more ofthe subject methods are effective in reducing antigen specific IgG3and/or IgGM production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold,7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold,750-fold, or about 1000-fold or more.

In one aspect, one of more of the subject methods are effective inameliorating symptoms associated with rheumatoid arthritis including,but not limited to a reduction in the swelling of joints, a reduction inserum anti-collagen levels, and/or a reduction in joint pathology suchas bone resorption, cartilage damage, pannus, and/or inflammation. Inanother aspect, the subject methods are effective in reducing ankleinflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, or60%, or about 75% to 90%. In another aspect, the subject methods areeffective in reducing knee inflammation by at least about 2%, 5%, 10%,15%, 20%, 25%, 30%, 50%, or 60%, or about 75% to 90% or more. In stillanother aspect, the subject methods are effective in reducing serumanti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%,25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, or 87%, or about 90% or more. Inanother aspect, the subject methods are effective in reducing anklehistopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 75%, 80%, or 90%, or more. In still another aspect, the subjectmethods are effective in reducing knee histopathology scores by about5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, or 90%, or more.

In some embodiments, provided herein are methods for treating disordersor conditions in which the δ isoform of PI3K is implicated to a greaterextent than other PI3K isoforms such as PI3K-α and/or PI3K-β. In someembodiments, provided herein are methods for treating disorders orconditions in which the γ isoform of PI3K is implicated to a greaterextent than other PI3K isoforms such as PI3K-α and/or PI3K-β. Selectiveinhibition of PI3K-δ and/or PI3K-γ can provide advantages over usingless selective compounds which inhibit PI3K-α and/or PI3K-β, such as animproved side effects profile or lessened reduction in the ability toreduce a bacterial, viral, and/or fungal infection.

In other embodiments, provided herein are methods of using a compoundprovided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, to treat respiratorydiseases including, but not limited to, diseases affecting the lobes oflung, pleural cavity, bronchial tubes, trachea, upper respiratory tract,or the nerves and muscle for breathing. For example, methods areprovided to treat obstructive pulmonary disease. Chronic obstructivepulmonary disease (COPD) is an umbrella term for a group of respiratorytract diseases that are characterized by airflow obstruction orlimitation. Conditions included in this umbrella term include, but arenot limited to: chronic bronchitis, emphysema, and bronchiectasis.

In another embodiment, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein is used forthe treatment of asthma. Also, a compound provided herein, or apharmaceutically acceptable form thereof, or a pharmaceuticalcomposition described herein, can be used for the treatment ofendotoxemia and sepsis. In one embodiment, the compounds orpharmaceutical compositions described herein are used to for thetreatment of rheumatoid arthritis (RA). In yet another embodiment, thecompounds or pharmaceutical compositions described herein is used forthe treatment of contact or atopic dermatitis. Contact dermatitisincludes irritant dermatitis, phototoxic dermatitis, allergicdermatitis, photoallergic dermatitis, contact urticaria, systemiccontact-type dermatitis and the like. Irritant dermatitis can occur whentoo much of a substance is used on the skin of when the skin issensitive to certain substance. Atopic dermatitis, sometimes calledeczema, is a kind of dermatitis, an atopic skin disease.

In some embodiments, the disclosure provides a method of treatingdiseases related to vasculogenesis or angiogenesis in a subject thatcomprises administering to said subject a therapeutically effectiveamount of a compound provided herein, or a pharmaceutically acceptableform (e.g., pharmaceutically acceptable salts, hydrates, solvates,isomers, prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein. In some embodiments, saidmethod is for treating a disease selected from tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis and chronicinflammatory demyelinating polyneuropathy, atherosclerosis, inflammatorybowel disease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes, diabetic retinopathy, retinopathy of prematurity, age-relatedmacular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

In addition, the compounds described herein can be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

In some embodiments, provided herein is a method of treating acardiovascular disease in a subject that comprises administering to saidsubject a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or a pharmaceuticalcomposition as provided herein. Examples of cardiovascular conditionsinclude, but are not limited to, atherosclerosis, restenosis, vascularocclusion and carotid obstructive disease.

In some embodiments, the disclosure relates to a method of treatingdiabetes in a subject that comprises administering to said subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein.

In addition, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can be usedto treat acne. In certain embodiments, the inflammatory condition and/orimmune disorder is a skin condition. In some embodiments, the skincondition is pruritus (itch), psoriasis, eczema, burns or dermatitis. Incertain embodiments, the skin condition is psoriasis. In certainembodiments, the skin condition is pruritis.

In certain embodiments, the inflammatory disorder and/or the immunedisorder is a gastrointestinal disorder. In some embodiments, thegastrointestinal disorder is selected from gastrointestinal disorder(e.g., selected from peptic ulcers, regional enteritis, diverticulitis,gastrointestinal bleeding, eosinophilic gastrointestinal disorders(e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis, eosinophilic colitis), gastritis, diarrhea,gastroesophageal reflux disease (GORD, or its synonym GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis) andinflammatory bowel syndrome (IBS)). In certain embodiments, thegastrointestinal disorder is inflammatory bowel disease (IBD).

Further, a compound provided herein, or a pharmaceutically acceptableform (e.g., pharmaceutically acceptable salts, hydrates, solvates,isomers, prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, can be used for thetreatment of glomerulonephritis. Glomerulonephritis is a primary orsecondary autoimmune renal disease characterized by inflammation of theglomeruli. It can be asymptomatic, or present with hematuria and/orproteinuria. There are many recognized types, divided in acute, subacuteor chronic glomerulonephritis. Causes are infectious (bacterial, viralor parasitic pathogens), autoimmune or paraneoplastic.

In some embodiments, provided herein are compounds, or pharmaceuticallyacceptable forms (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, for thetreatment of multiorgan failure. Also provided herein are compounds, orpharmaceutically acceptable forms (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of liver diseases (including diabetes), gall bladderdisease (including gallstones), pancreatitis or kidney disease(including proliferative glomerulonephritis and diabetes-induced renaldisease) or pain in a subject.

In some embodiments, provided herein are compounds, or pharmaceuticallyacceptable forms (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, for theprevention of blastocyte implantation in a subject.

In some embodiments, provided herein are compounds, or pharmaceuticallyacceptable forms (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, for thetreatment of disorders involving platelet aggregation or plateletadhesion, including, but not limited to, Idiopathic thrombocytopenicpurpura, Bernard-Soulier syndrome, Glanzmann's thrombasthenia, Scott'ssyndrome, von Willebrand disease, Hermansky-Pudlak Syndrome, and Grayplatelet syndrome.

In some embodiments, provided herein are compounds, or pharmaceuticallyacceptable forms (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, for thetreatment of a disease which is skeletal muscle atrophy, skeletal ormuscle hypertrophy. In some embodiments, provided herein are compounds,or pharmaceutically acceptable forms (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of disorders that include, but are not limited to,cancers as discussed herein, transplantation-related disorders (e.g.,lowering rejection rates, graft-versus-host disease, etc.), muscularsclerosis (MS), allergic disorders (e.g., arthritis, allergicencephalomyelitis) and other immunosuppressive-related disorders,metabolic disorders (e.g., diabetes), reducing intimal thickeningfollowing vascular injury, and misfolded protein disorders (e.g.,Alzheimer's Disease, Gaucher's Disease, Parkinson's Disease,Huntington's Disease, cystic fibrosis, macular degeneration, retinitispigmentosa, and prion disorders) (as mTOR inhibition can alleviate theeffects of misfolded protein aggregates). The disorders also includehamartoma syndromes, such as tuberous sclerosis and Cowden Disease (alsotermed Cowden syndrome and multiple hamartoma syndrome).

Additionally, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can be usedfor the treatment of bursitis, lupus, acute disseminatedencephalomyelitis (ADEM), Addison's disease, antiphospholipid antibodysyndrome (APS), amyloidosis (including systemic and localizedamyloidosis; and primary and secondary amyloidosis), aplastic anemia,autoimmune hepatitis, coeliac disease, crohn's disease, diabetesmellitus (type 1), eosinophilic gastroenterides, goodpasture's syndrome,graves' disease, guillain-barré syndrome (GBS), hashimoto's disease,inflammatory bowel disease, lupus erythematosus (including cutaneouslupus erythematosus and systemic lupus erythematosus), myastheniagravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, ord'sthyroiditis, ostheoarthritis, uveoretinitis, pemphigus, polyarthritis,primary biliary cirrhosis, reiter's syndrome, takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, wegener'sgranulomatosis, alopecia universalis, chagas' disease, chronic fatiguesyndrome, dysautonomia, endometriosis, hidradenitis suppurativa,interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma,ulcerative colitis, vitiligo, vulvodynia, appendicitis, arteritis,arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis,cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis,cystitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis,hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis,myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis,orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, uveitis (e.g., ocularuveitis), vaginitis, vasculitis, or vulvitis.

In another aspect, provided herein are methods of disrupting thefunction of a leukocyte or disrupting a function of an osteoclast. Themethod includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound provided herein.

In another aspect, provided herein are methods for the treatment of anophthalmic disease by administering one or more of compounds providedherein, or pharmaceutically acceptable forms thereof, or pharmaceuticalcompositions as provided herein, to the eye of a subject.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: Crohn's disease; cutaneous lupus;multiple sclerosis; rheumatoid arthritis; and systemic lupuserythematosus.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: ankylosing spondylitis; chronicobstructive pulmonary disease; myasthenia gravis; ocular uveitis,psoriasis; and psoriatic arthritis.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: adult-onset Still's disease;inflammatory alopecia; amyloidosis; antiphospholipid syndrome;autoimmune hepatitis; autoimmune skin disease, Behcet's disease; chronicinflammatory demyelinating polyneuropathy; eosinophilic gastroenteritis;inflammatory myopathies, pemphigus, polymyalgia rheumatica; relapsingpolychondritis; Sjorgen's syndrome; temporal arthritis; ulcerativecolitis; vasculis; vitiligo, and Wegner's granulomatosis.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: gout flare; sacoidosis; and systemicsclerosis.

In certain embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: asthma; arthritis (e.g., rheumatoidarthritis and psoriatic arthritis); psoriasis; scleroderma; myositis(e.g., dermatomyositis); lupus (e.g., cutaneous lupus erythematosus(“CLE”) or systemic lupus erythematosus (“SLE”)); or Sjögren's syndrome.

Efficacy of a compound provided herein in treating, preventing and/ormanaging the disease or disorder can be tested using various animalmodels known in the art. For example: efficacy in treating, preventingand/or managing asthma can be assessed using ova induced asthma modeldescribed, for example, in Lee et al. (2006) J Allergy Clin Immunol118(2):403-9; efficacy in treating, preventing and/or managing arthritis(e.g., rheumatoid or psoriatic arthritis) can be assessed usingautoimmune animal models described, for example, in Williams et al.(2010) Chem Biol, 17(2):123-34, WO 2009/088986, WO2009/088880, and WO2011/008302; efficacy in treating, preventing and/or managing psoriasiscan be assessed using transgenic or knockout mouse model with targetedmutations in epidermis, vasculature or immune cells, mouse modelresulting from spontaneous mutations, and immuno-deficient mouse modelwith xenotransplantation of human skin or immune cells, all of which aredescribed, for example, in Boehncke et al. (2007) Clinics inDermatology, 25: 596-605; efficacy in treating, preventing and/ormanaging fibrosis or fibrotic condition can be assessed using theunilateral ureteral obstruction model of renal fibrosis (see Chevalieret al., Kidney International (2009) 75:1145-1152), the bleomycin inducedmodel of pulmonary fibrosis (see Moore and Hogaboam, Am. J. Physiol.Lung. Cell. Mol. Physiol. (2008) 294:L152-L160), a variety ofliver/biliary fibrosis models (see Chuang et al., Clin Liver Dis (2008)12:333-347 and Omenetti, A. et al. (2007) Laboratory Investigation87:499-514 (biliary duct-ligated model)), or a number of myelofibrosismouse models (see Varicchio, L. et al. (2009) Expert Rev. Hematol.2(3):315-334); efficacy in treating, preventing and/or managingscleroderma can be assessed using mouse model induced by repeated localinjections of bleomycin (“BLM”) described, for example, in Yamamoto etal. (1999) J Invest Dermatol 112: 456-462; efficacy in treating,preventing and/or managing dermatomyositis can be assessed usingmyositis mouse model induced by immunization with rabbit myosindescribed, for example, in Phyanagi et al. (2009) Arthritis &Rheumatism, 60(10): 3118-3127; efficacy in treating, preventing and/ormanaging lupus (e.g., CLE or SLE) can be assessed using various animalmodels described, for example, in Ghoreishi et al. (2009) Lupus, 19:1029-1035, Ohl et al. (2011) Journal of Biomedicine and Biotechnology,Article ID 432595 (14 pages), Xia et al. (2011) Rheumatology,50:2187-2196, Pau et al. (2012) PLoS ONE, 7(5):e36761 (15 pages),Mustafa et al. (2011) Toxicology, 290:156-168, Ichikawa et al. (2012)Arthritis and Rheumatism, 62(2): 493-503, Ouyang et al. (2012) J MolMed, DOI 10.1007/s00109-012-0866-3 (10 pages), Rankin et al. (2012)Journal of Immunology, 188:1656-1667; and efficacy in treating,preventing and/or managing Sjögren's syndrome can be assessed usingvarious mouse models described, for example, in Chiorini et al. (2009)Journal of Autoimmunity, 33: 190-196.

In one embodiment, provided herein is a method of treating, preventingand/or managing asthma. As used herein, “asthma” encompasses airwayconstriction regardless of the cause. Common triggers of asthma include,but are not limited to, exposure to an environmental stimulants (e.g.,allergens), cold air, warm air, perfume, moist air, exercise orexertion, and emotional stress. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith asthma. Examples of the symptoms include, but are not limited to,severe coughing, airway constriction and mucus production.

In one embodiment, provided herein is a method of treating, preventingand/or managing arthritis. As used herein, “arthritis” encompasses alltypes and manifestations of arthritis. Examples include, but are notlimited to, crystalline arthritis, osteoarthritis, psoriatic arthritis,gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter'sarthritis. In one embodiment, the disease or disorder is rheumatoidarthritis. In another embodiment, the disease or disorder is psoriaticarthritis. Also provided herein is a method of treating, preventingand/or managing one or more symptoms associated with arthritis. Examplesof the symptoms include, but are not limited to, joint pain, whichprogresses into joint deformation, or damages in body organs such as inblood vessels, heart, lungs, skin, and muscles.

In one embodiment, provided herein is a method of treating, preventingand/or managing psoriasis. As used herein, “psoriasis” encompasses alltypes and manifestations of psoriasis. Examples include, but are notlimited to, plaque psoriasis (e.g., chronic plaque psoriasis, moderateplaque psoriasis and severe plaque psoriasis), guttate psoriasis,inverse psoriasis, pustular psoriasis, pemphigus vulgaris, erythrodermicpsoriasis, psoriasis associated with inflammatory bowel disease (IBD),and psoriasis associated with rheumatoid arthritis (RA). Also providedherein is a method of treating, preventing and/or managing one or moresymptoms associated with psoriasis. Examples of the symptoms include,but are not limited to: red patches of skin covered with silvery scales;small scaling spots; dry, cracked skin that may bleed; itching; burning;soreness; thickened, pitted or ridged nails; and swollen and stiffjoints.

In one embodiment, provided herein is a method of treating, preventingand/or managing fibrosis and fibrotic condition. As used herein,“fibrosis” or “fibrotic condition encompasses all types andmanifestations of fibrosis or fibrotic condition. Examples include, butare not limited to, formation or deposition of tissue fibrosis; reducingthe size, cellularity (e.g., fibroblast or immune cell numbers),composition; or cellular content, of a fibrotic lesion; reducing thecollagen or hydroxyproline content, of a fibrotic lesion; reducingexpression or activity of a fibrogenic protein; reducing fibrosisassociated with an inflammatory response; decreasing weight lossassociated with fibrosis; or increasing survival.

In certain embodiments, the fibrotic condition is primary fibrosis. Inone embodiment, the fibrotic condition is idiopathic. In otherembodiments, the fibrotic condition is associated with (e.g., issecondary to) a disease (e.g., an infectious disease, an inflammatorydisease, an autoimmune disease, a malignant or cancerous disease, and/ora connective disease); a toxin; an insult (e.g., an environmental hazard(e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarettesmoking, a wound); a medical treatment (e.g., surgical incision,chemotherapy or radiation), or a combination thereof.

In some embodiments, the fibrotic condition is associated with anautoimmune disease selected from scleroderma or lupus, e.g., systemiclupus erythematosus. In some embodiments, the fibrotic condition issystemic. In some embodiments, the fibrotic condition is systemicsclerosis (e.g., limited systemic sclerosis, diffuse systemic sclerosis,or systemic sclerosis sine scleroderma), nephrogenic systemic fibrosis,cystic fibrosis, chronic graft vs. host disease, or atherosclerosis.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the lung, a fibrotic condition of the liver, a fibrotic condition ofthe heart or vasculature, a fibrotic condition of the kidney, a fibroticcondition of the skin, a fibrotic condition of the gastrointestinaltract, a fibrotic condition of the bone marrow or a hematopoietictissue, a fibrotic condition of the nervous system, a fibrotic conditionof the eye, or a combination thereof.

In other embodiment, the fibrotic condition affects a tissue chosen fromone or more of muscle, tendon, cartilage, skin (e.g., skin epidermis orendodermis), cardiac tissue, vascular tissue (e.g., artery, vein),pancreatic tissue, lung tissue, liver tissue, kidney tissue, uterinetissue, ovarian tissue, neural tissue, testicular tissue, peritonealtissue, colon, small intestine, biliary tract, gut, bone marrow,hematopoietic tissue, or eye (e.g., retinal) tissue.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe eye. In some embodiments, the fibrotic condition is glaucoma,macular degeneration (e.g., age-related macular degeneration), macularedema (e.g., diabetic macular edema), retinopathy (e.g., diabeticretinopathy), or dry eye disease.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the lung. In certain embodiments, the fibrotic condition of the lungis chosen from one or more of: pulmonary fibrosis, idiopathic pulmonaryfibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lungdisease, cryptogenic fibrosing alveolitis (CFA), bronchiectasis, andscleroderma lung disease. In one embodiment, the fibrosis of the lung issecondary to a disease, a toxin, an insult, a medical treatment, or acombination thereof. For example, the fibrosis of the lung can beassociated with (e.g., secondary to) one or more of: a disease processsuch as asbestosis and silicosis; an occupational hazard; anenvironmental pollutant; cigarette smoking; an autoimmune connectivetissue disorders (e.g., rheumatoid arthritis, scleroderma and systemiclupus erythematosus (SLE)); a connective tissue disorder such assarcoidosis; an infectious disease, e.g., infection, particularlychronic infection; a medical treatment, including but not limited to,radiation therapy, and drug therapy, e.g., chemotherapy (e.g., treatmentwith as bleomycin, methotrexate, amiodarone, busulfan, and/ornitrofurantoin). In one embodiment, the fibrotic condition of the lungtreated with the methods of the invention is associated with (e.g.,secondary to) a cancer treatment, e.g., treatment of a cancer (e.g.,squamous cell carcinoma, testicular cancer, Hodgkin's disease withbleomycin). In one embodiment, the fibrotic condition of the lung isassociated with an autoimmune connective tissue disorder (e.g.,scleroderma or lupus, e.g., SLE).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the liver. In certain embodiments, the fibrotic condition of theliver is chosen from one or more of: fatty liver disease, steatosis(e.g., nonalcoholic steatohepatitis (NASH), cholestatic liver disease(e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol inducedliver fibrosis, biliary duct injury, biliary fibrosis, orcholangiopathies. In other embodiments, hepatic or liver fibrosisincludes, but is not limited to, hepatic fibrosis associated withalcoholism, viral infection, e.g., hepatitis (e.g., hepatitis C, B orD), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD),progressive massive fibrosis, exposure to toxins or irritants (e.g.,alcohol, pharmaceutical drugs and environmental toxins).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the heart. In certain embodiments, the fibrotic condition of theheart is myocardial fibrosis (e.g., myocardial fibrosis associated withradiation myocarditis, a surgical procedure complication (e.g.,myocardial post-operative fibrosis), infectious diseases (e.g., Chagasdisease, bacterial, trichinosis or fungal myocarditis)); granulomatous,metabolic storage disorders (e.g., cardiomyopathy, hemochromatosis);developmental disorders (e.g., endocardial fibroelastosis);arteriosclerotic, or exposure to toxins or irritants (e.g., drug inducedcardiomyopathy, drug induced cardiotoxicity, alcoholic cardiomyopathy,cobalt poisoning or exposure). In certain embodiments, the myocardialfibrosis is associated with an inflammatory disorder of cardiac tissue(e.g., myocardial sarcoidosis). In some embodiments, the fibroticcondition is a fibrotic condition associated with a myocardialinfarction. In some embodiments, the fibrotic condition is a fibroticcondition associated with congestive heart failure.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the kidney. In certain embodiments, the fibrotic condition of thekidney is chosen from one or more of: renal fibrosis (e.g., chronickidney fibrosis), nephropathies associated with injury/fibrosis (e.g.,chronic nephropathies associated with diabetes (e.g., diabeticnephropathy)), lupus, scleroderma of the kidney, glomerular nephritis,focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosisassociated with human chronic kidney disease (CKD), chronic progressivenephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction,chronic uremia, chronic interstitial nephritis, radiation nephropathy,glomerulosclerosis, progressive glomerulonephrosis (PGN),endothelial/thrombotic microangiopathy injury, HIV-associatednephropathy, or fibrosis associated with exposure to a toxin, anirritant, or a chemotherapeutic agent. In one embodiment, the fibroticcondition of the kidney is scleroderma of the kidney. In someembodiments, the fibrotic condition of the kidney is transplantnephropathy, diabetic nephropathy, lupus nephritis, or focal segmentalglomerulosclerosis (FSGS).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the skin. In certain embodiments, the fibrotic condition of the skinis chosen from one or more of: skin fibrosis (e.g., hypertrophicscarring, keloid), scleroderma, nephrogenic systemic fibrosis (e.g.,resulting after exposure to gadolinium (which is frequently used as acontrast substance for MRIs) in patients with severe kidney failure),and keloid.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the gastrointestinal tract. In certain embodiments, the fibroticcondition is chosen from one or more of: fibrosis associated withscleroderma; radiation induced gut fibrosis; fibrosis associated with aforegut inflammatory disorder such as Barrett's esophagus and chronicgastritis, and/or fibrosis associated with a hindgut inflammatorydisorder, such as inflammatory bowel disease (IBD), ulcerative colitisand Crohn's disease. In some embodiments, the fibrotic condition of thegastrointestinal tract is fibrosis associated with scleroderma.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the bone marrow or a hematopoietic tissue. In certain embodiments,the fibrotic condition of the bone marrow is an intrinsic feature of achronic myeloproliferative neoplasm of the bone marrow, such as primarymyelofibrosis (also referred to herein as agnogenic myeloid metaplasiaor chronic idiopathic myelofibrosis). In other embodiments, the bonemarrow fibrosis is associated with (e.g., is secondary to) a malignantcondition or a condition caused by a clonal proliferative disease. Inother embodiments, the bone marrow fibrosis is associated with ahematologic disorder (e.g., a hematologic disorder chosen from one ormore of polycythemia vera, essential thrombocythemia, myelodysplasia,hairy cell leukemia, lymphoma (e.g., Hodgkin or non-Hodgkin lymphoma),multiple myeloma or chronic myelogeneous leukemia (CML)). In yet otherembodiments, the bone marrow fibrosis is associated with (e.g.,secondary to) a non-hematologic disorder (e.g., a non-hematologicdisorder chosen from solid tumor metastasis to bone marrow, anautoimmune disorder (e.g., systemic lupus erythematosus, scleroderma,mixed connective tissue disorder, or polymyositis), an infection (e.g.,tuberculosis), or secondary hyperparathyroidism associated with vitaminD deficiency. In some embodiments, the fibrotic condition is idiopathicor drug-induced myelofibrosis. In some embodiments, the fibroticcondition of the bone marrow or hematopoietic tissue is associated withsystemic lupus erythematosus or scleroderma.

In one embodiment, provided herein is a method of treating, preventingand/or managing scleroderma. Scleroderma is a group of diseases thatinvolve hardening and tightening of the skin and/or other connectivetissues. Scleroderma may be localized (e.g., affecting only the skin) orsystemic (e.g., affecting other systems such as, e.g., blood vesselsand/or internal organs). Common symptoms of scleroderma includeRaynaud's phenomenon, gastroesophageal reflux disease, and skin changes(e.g., swollen fingers and hands, or thickened patches of skin). In someembodiments, the scleroderma is localized, e.g., morphea or linearscleroderma. In some embodiments, the condition is a systemic sclerosis,e.g., limited systemic sclerosis, diffuse systemic sclerosis, orsystemic sclerosis sine scleroderma.

Localized scleroderma (localized cutaneous fibrosis) includes morpheaand linear scleroderma. Morphea is typically characterized byoval-shaped thickened patches of skin that are white in the middle, witha purple border. Linear scleroderma is more common in children. Symptomsof linear scleroderma may appear mostly on one side of the body. Inlinear scleroderma, bands or streaks of hardened skin may develop on oneor both arms or legs or on the forehead. En coup de sabre (frontallinear scleroderma or morphea en coup de sabre) is a type of localizedscleroderma typically characterized by linear lesions of the scalp orface.

Systemic scleroderma (systemic sclerosis) includes, e.g., limitedsystemic sclerosis (also known as limited cutaneous systemic sclerosis,or CREST syndrome), diffuse systemic sclerosis (also known as diffusecutaneous systemic sclerosis), and systemic sclerosis sine scleroderma.CREST stands for the following complications that may accompany limitedscleroderma: calcinosis (e.g., of the digits), Raynaud's phenomenon,esophageal dysfunction, sclerodactyl), and telangiectasias. Typically,limited scleroderma involves cutaneous manifestations that mainly affectthe hands, arms, and face. Limited and diffuse subtypes aredistinguished based on the extent of skin involvement, with sparing ofthe proximal limbs and trunk in limited disease. See, e.g., Denton, C.P. et al. (2006), Nature Clinical Practice Rheumatology, 2(3):134-143.The limited subtype also typically involves a long previous history ofRaynaud's phenomenon, whereas in the diffuse subtype, onset of Raynaud'sphenomenon can be simultaneous with other manifestations or might occurlater. Both limited and diffuse subtypes may involve internal organs.Typical visceral manifestations of limited systemic sclerosis includeisolated pulmonary hypertension, severe bowel involvement, and pulmonaryfibrosis. Typical visceral manifestations of diffuse systemic sclerosisinclude renal crisis, lung fibrosis, and cardiac disease. Diffusesystemic sclerosis typically progresses rapidly and affects a large areaof the skin and one or more internal organs (e.g., kidneys, esophagus,heart, or lungs). Systemic sclerosis sine scleroderma is a rare disorderin which patients develop vascular and fibrotic damage to internalorgans in the absence of cutaneous sclerosis.

In one embodiment, provided herein is a method of treating, preventingand/or managing inflammatory myopathies. As used herein, “inflammatorymyopathies” encompass all types and manifestations of inflammatorymyopathies. Examples include, but are not limited to, muscle weakness(e.g., proximal muscle weakness), skin rash, fatigue after walking orstanding, tripping or falling, dysphagia, dysphonia, difficultybreathing, muscle pain, tender muscles, weight loss, low-grade fever,inflamed lungs, light sensitivity, calcium deposits (calcinosis) underthe skin or in the muscle, as well as biological concomitants ofinflammatory myopathies as disclosed herein or as known in the art.Biological concomitants of inflammatory myopathies (e.g.,dermatomyositis) include, e.g., altered (e.g., increased) levels ofcytokines (e.g., Type I interferons (e.g., IFN-α and/or IFN-β),interleukins (e.g., IL-6, IL-10, IL-15, IL-17 and IL-18), and TNF-α),TGF-β, B-cell activating factor (BAFF), overexpression of IFN induciblegenes (e.g., Type I IFN inducible genes). Other biological concomitantsof inflammatory myopathies can include, e.g., an increased erythrocytesedimentation rate (ESR) and/or elevated level of creatine kinase.Further biological concomitants of inflammatory myopathies can includeautoantibodies, e.g., anti-synthetase autoantibodies (e.g., anti-Jo1antibodies), anti-signal recognition particle antibodies (anti-SRP),anti-Mi-2 antibodies, anti-p155 antibodies, anti-PM/Sci antibodies, andanti-RNP antibodies.

The inflammatory myopathy can be an acute inflammatory myopathy or achronic inflammatory myopathy. In some embodiments, the inflammatorymyopathy is a chronic inflammatory myopathy (e.g., dermatomyositis,polymyositis, or inclusion body myositis). In some embodiments, theinflammatory myopathy is caused by an allergic reaction, another disease(e.g., cancer or a connective tissue disease), exposure to a toxicsubstance, a medicine, or an infectious agent (e.g., a virus). In someembodiments, the inflammatory myopathy is associated with lupus,rheumatoid arthritis, or systemic sclerosis. In some embodiments, theinflammatory myopathy is idiopathic. In some embodiments, theinflammatory myopathy is selected from polymyositis, dermatomyositis,inclusion body myositis, and immune-mediated necrotizing myopathy. Insome embodiments, the inflammatory myopathy is dermatomyositis.

In another embodiment, provided herein is a method of treating,preventing and/or managing a skin condition (e.g., a dermatitis). Insome embodiments, the methods provided herein can reduce symptomsassociated with a skin condition (e.g., itchiness and/or inflammation).In some such embodiments, the compound provided herein is administeredtopically (e.g., as a topical cream, eye-drop, nose drop or nasalspray). In some such embodiments, the compound is a PI3K delta inhibitor(e.g., a PI3K inhibitor that demonstrates greater inhibition of PI3Kdelta than of other PI3K isoforms). In some embodiments, the PI3K deltainhibitor prevents mast cell degranulation.

As used herein, “skin condition” includes any inflammatory condition ofthe skin (e.g., eczema or dermatitis, e.g., contact dermatitis, atopicdermatitis, dermatitis herpetiformis, seborrheic dermatitis, nummulardermatitis, stasis dermatitis, perioral dermatitis), as well asaccompanying symptoms (e.g., skin rash, itchiness (pruritis), swelling(edema), hay fever, anaphalaxis). Frequently, such skin conditions arecaused by an allergen. As used herein, a “skin condition” also includes,e.g., skin rashes (e.g., allergic rashes, e.g., rashes resulting fromexposure to allergens such as poison ivy, poison oak, or poison sumac,or rashes caused by other diseases or conditions), insect bites, minorburns, sunburn, minor cuts, and scrapes. In some embodiments, thesymptom associated with inflammatory myopathy, or the skin condition orsymptom associated with the skin condition, is a skin rash or itchiness(pruritis) caused by a skin rash.

The skin condition (e.g., the skin rash) may be spontaneous, or it maybe induced, e.g., by exposure to an allergen (e.g., poison ivy, poisonoak, or poison sumac), drugs, food, insect bite, inhalants, emotionalstress, exposure to heat, exposure to cold, or exercise. In someembodiments, the skin condition is a skin rash (e.g., a pruritic rash,e.g., utricaria). In some embodiments, the skin condition is an insectbite. In some embodiments, the skin condition is associated with anotherdisease (e.g., an inflammatory myopathy, e.g., dermatomyositis).

In some embodiments, the subject (e.g., the subject in need of treatmentfor an inflammatory myopathy and/or a skin condition) exhibits anelevated level or elevated activity of IFN-α, TNF-α, IL-6, IL-8, IL-1,or a combination thereof. In certain embodiments, the subject exhibitsan elevated level of IFN-α. In some embodiments, treating (e.g.,decreasing or inhibiting) the inflammatory myopathy, or the skincondition, comprises inhibiting (e.g., decreasing a level of, ordecreasing a biological activity of) one or more of IFN-α, TNF-α, IL-6,IL-8, or IL-1 in the subject or in a sample derived from the subject. Insome embodiments, the method decreases a level of IFN-α, TNF-α, IL-6,IL-8, or IL-1 in the subject or in a sample derived from the subject. Insome embodiments, the method decreases a level of IFN-α in the subjector in a sample derived from the subject. In some embodiments, the levelof IFN-α, TNF-α, IL-6, IL-8, or IL-1 is the level assessed in a sampleof whole blood or PBMCs. In some embodiments, the level of IFN-α, TNF-α,IL-6, IL-8, or IL-1 is the level assessed in a sample obtained by a skinbiopsy or a muscle biopsy. In some embodiments, the sample is obtainedby a skin biopsy.

In one embodiment, provided herein is a method of treating, preventingand/or managing myositis. As used herein, “myositis” encompasses alltypes and manifestations of myositis. Examples include, but are notlimited to, myositis ossificans, fibromyositis, idiopathic inflammatorymyopathies, dermatomyositis, juvenile dermatomyositis, polymyositis,inclusion body myositis and pyomyositis. In one embodiment, the diseaseor disorder is dermatomyositis. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith myositis. Examples of the symptoms include, but are not limited to:muscle weakness; trouble lifting arms; trouble swallowing or breathing;muscle pain; muscle tenderness; fatigue; fever; lung problems;gastrointestinal ulcers; intestinal perforations; calcinosis under theskin; soreness; arthritis; weight loss; and rashes.

In one embodiment, provided herein is a method of treating, preventingand/or managing lupus. As used herein, “lupus” refers to all types andmanifestations of lupus. Examples include, but are not limited to,systemic lupus erythematosus; lupus nephritis; cutaneous manifestations(e.g., manifestations seen in cutaneous lupus erythematosus, e.g., askin lesion or rash); CNS lupus; cardiovascular, pulmonary, hepatic,hematological, gastrointestinal and musculoskeletal manifestations;neonatal lupus erythematosus; childhood systemic lupus erythematosus;drug-induced lupus erythematosus; anti-phospholipid syndrome; andcomplement deficiency syndromes resulting in lupus manifestations. Inone embodiment, the lupus is systemic lupus erythematosus (SLE),cutaneous lupus erythematosus (CLE), drug-induced lupus, or neonatallupus. In another embodiment, the lupus is a CLE, e.g., acute cutaneouslupus erythematosus (ACLE), subacute cutaneous lupus erythematosus(SCLE), intermittent cutaneous lupus erythematosus (also known as lupuserythematosus tumidus (LET)), or chronic cutaneous lupus. In someembodiments, the intermittent CLE is chronic discloid lupuserythematosus (CDLE) or lupus erythematosus profundus (LEP) (also knownas lupus erythematosus panniculitis). Types, symptoms, and pathogenesisof CLE are described, for example, in Wenzel et al. (2010), Lupus, 19,1020-1028.

In one embodiment, provided herein is a method of treating, preventingand/or managing Sjögren's syndrome. As used herein, “Sjögren's syndrome”refers to all types and manifestations of Sjögren's syndrome. Examplesinclude, but are not limited to, primary and secondary Sjögren'ssyndrome. Also provided herein is a method of treating, preventingand/or managing one or more symptoms associated with Sjögren's syndrome.Examples of the symptoms include, but are not limited to: dry eyes; drymouth; joint pain; swelling; stiffness; swollen salivary glands; skinrashes; dry skin; vaginal dryness; persistent dry cough; and prolongedfatigue.

In some embodiments, a symptom associated with the disease or disorderprovided herein is reduced by at least 10%, at least 20%, at least 30%,at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, or at least 95% relative to a control level. The controllevel includes any appropriate control as known in the art. For example,the control level can be the pre-treatment level in the sample orsubject treated, or it can be the level in a control population (e.g.,the level in subjects who do not have the disease or disorder or thelevel in samples derived from subjects who do not have the disease ordisorder). In some embodiments, the decrease is statisticallysignificant, for example, as assessed using an appropriate parametric ornon-parametric statistical comparison.

Combination Therapy

In some embodiments, provided herein are methods for combinationtherapies in which an agent known to modulate other pathways, or othercomponents of the same pathway, or even overlapping sets of targetenzymes are used in combination with a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. In one aspect, such therapy includes, but is notlimited to, the combination of the subject compound withchemotherapeutic agents, therapeutic antibodies, and radiationtreatment, to provide a synergistic or additive therapeutic effect.

In one aspect, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can presentsynergistic or additive efficacy when administered in combination withagents that inhibit IgE production or activity. Such combination canreduce the undesired effect of high level of IgE associated with the useof one or more PI3K-δ inhibitors, if such effect occurs. This can beparticularly useful in treatment of autoimmune and inflammatorydisorders (AIID) such as rheumatoid arthritis. Additionally, theadministration of PI3K-δ, PI3K-γ, or PI3K-δ/γ inhibitors as providedherein in combination with inhibitors of mTOR can also exhibit synergythrough enhanced inhibition of the PI3K pathway.

In a separate but related aspect, provided herein is a combinationtreatment of a disease associated with PI3K-δ comprising administeringto a PI3K-δ inhibitor and an agent that inhibits IgE production oractivity. Other exemplary PI3K-δ inhibitors are applicable for thiscombination and they are described in, e.g., U.S. Pat. No. 6,800,620,incorporated herein by reference. Such combination treatment isparticularly useful for treating autoimmune and inflammatory diseases(AIID) including, but not limited to rheumatoid arthritis.

Agents that inhibit IgE production are known in the art and theyinclude, but are not limited to, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

For treatment of autoimmune diseases, a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein, can be used in combination with commonly prescribed drugsincluding, but not limited to, Enbrel®, Remicade®, Humira®, Avonex®, andRebif®. For treatment of respiratory diseases, the subject compounds, orpharmaceutically acceptable forms thereof, or pharmaceuticalcompositions, can be administered in combination with commonlyprescribed drugs including, but not limited to, Xolair®, Advair®,Singulair®, and Spiriva®.

The compounds as provided herein, or pharmaceutically acceptable forms(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be formulated oradministered in conjunction with other agents that act to relieve thesymptoms of inflammatory conditions such as encephalomyelitis, asthma,and the other diseases described herein. These agents includenon-steroidal anti-inflammatory drugs (NSAIDs), e.g., acetylsalicylicacid; ibuprofen; naproxen; indomethacin; nabumetone; tolmetin; etc.Corticosteroids are used to reduce inflammation and suppress activity ofthe immune system. An exemplary drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) can also be usedin some individuals with lupus. They can be prescribed for skin andjoint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide(Cytoxan) suppress inflammation and tend to suppress the immune system.Other agents, e.g., methotrexate and cyclosporin are used to control thesymptoms of lupus. Anticoagulants are employed to prevent blood fromclotting rapidly. They range from aspirin at very low dose whichprevents platelets from sticking, to heparin/coumadin. Other compoundsused in the treatment of lupus include belimumab (Benlysta®).

In another aspect, provided herein is a pharmaceutical composition forinhibiting abnormal cell growth in a subject which comprises an amountof a compound provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, in combinationwith an amount of an anti-cancer agent (e.g., a chemotherapeutic agent).Many chemotherapeutics are presently known in the art and can be used incombination with a compound provided herein.

In some embodiments, the chemotherapeutic is selected from mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens. Non-limiting examples arechemotherapeutic agents, cytotoxic agents, and non-peptide smallmolecules such as Gleevec® (Imatinib Mesylate), Velcade® (bortezomib),Casodex (bicalutamide), Iressa®, and Adriamycin as well as a host ofchemotherapeutic agents. Non-limiting examples of chemotherapeuticagents include alkylating agents such as thiotepa and cyclosphosphamide(CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; BTK inhibitorssuch as ibrutinib (PCI-32765) and AVL-292; HDAC inhibitors such asvorinostat, romidepsin, panobinostat, valproic acid, belinostat,mocetinostat, abrexinostat, entinostat, SB939, resminostat, givinostat,CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215 andkevetrin; JAK/STAT inhibitors such as lestaurtinib, tofacitinib,ruxolitinib, pacritinib, CYT387, baricitinib, fostamatinib, GLPG0636,TG101348, INCB16562 and AZD1480; nitrogen mustards such as bedamustine,chlorambucil, chlornaphazine, cholophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard; nitrosureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, ranimustine; antibiotics such asaclacinomysins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin,Casodex™, chromomycins, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pralatrexate, pteropterin, trimetrexate; purine analogssuch as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,floxuridine, androgens such as calusterone, dromostanolone propionate,epitiostanol, mepitiostane, testolactone; anti-adrenals such asaminoglutethimide, mitotane, trilostane; folic acid replenisher such asfrolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinicacid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France) and ABRAXANE®(paclitaxel protein-bound particles); retinoic acid; esperamicins;capecitabine; and pharmaceutically acceptable forms (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) of any of the above.Also included as suitable chemotherapeutic cell conditioners areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens including for example tamoxifen(Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogs such ascisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO). Where desired, the compounds orpharmaceutical composition as provided herein can be used in combinationwith commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®,Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE,Abagovomab, Acridine carboxamide, Adecatumumab,17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib,3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide,Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenicherbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine,BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine,CBV (chemotherapy), Calyculin, Crizotinib, cell-cycle nonspecificantineoplastic agents, Dichloroacetic acid, Discodermolide,Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan,Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen,IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar,Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide,Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1,Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod,Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V,Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel,Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine,Uramustine, Vadimezan, Vinflunine, ZD6126, and Zosuquidar.

In some embodiments, the chemotherapeutic is selected from hedgehoginhibitors including, but not limited to IPI-926 (See U.S. Pat. No.7,812,164). Other suitable hedgehog inhibitors include, for example,those described and disclosed in U.S. Pat. No. 7,230,004, U.S. PatentApplication Publication No. 2008/0293754, U.S. Patent ApplicationPublication No. 2008/0287420, and U.S. Patent Application PublicationNo. 2008/0293755, the entire disclosures of which are incorporated byreference herein. Examples of other suitable hedgehog inhibitors includethose described in U.S. Patent Application Publication Nos. US2002/0006931, US 2007/0021493 and US 2007/0060546, and InternationalApplication Publication Nos. WO 2001/19800, WO 2001/26644, WO2001/27135, WO 2001/49279, WO 2001/74344, WO 2003/011219, WO2003/088970, WO 2004/020599, WO 2005/013800, WO 2005/033288, WO2005/032343, WO 2005/042700, WO 2006/028958, WO 2006/050351, WO2006/078283, WO 2007/054623, WO 2007/059157, WO 2007/120827, WO2007/131201, WO 2008/070357, WO 2008/110611, WO 2008/112913, and WO2008/131354, each incorporated herein by reference. Additional examplesof hedgehog inhibitors include, but are not limited to, GDC-0449 (alsoknown as RG3616 or vismodegib) described in, e.g., Von Hoff D. et al.,N. Engl. J. Med. 2009; 361(12):1164-72; Robarge K. D. et al., Bioorg MedChem Lett. 2009; 19(19):5576-81; Yauch, R. L. et al. (2009) Science 326:572-574; Sciencexpress: 1-3 (10.1126/science.1179386); Rudin, C. et al.(2009) New England J of Medicine 361-366 (10.1056/nejma0902903);BMS-833923 (also known as XL139) described in, e.g., in Siu L. et al.,J. Clin. Oncol. 2010; 28:15s (suppl; abstr 2501); and National Instituteof Health Clinical Trial Identifier No. NCT006701891; LDE-225 described,e.g., in Pan S. et al., ACS Med. Chem. Lett., 2010; 1(3): 130-134;LEQ-506 described, e.g., in National Institute of Health Clinical TrialIdentifier No. NCT01106508; PF-04449913 described, e.g., in NationalInstitute of Health Clinical Trial Identifier No. NCT00953758; Hedgehogpathway antagonists disclosed in U.S. Patent Application Publication No.2010/0286114; SMOi2-17 described, e.g., U.S. Patent ApplicationPublication No. 2010/0093625; SANT-1 and SANT-2 described, e.g., inRominger C. M. et al., J. Pharmacol. Exp. Ther. 2009; 329(3):995-1005;1-piperazinyl-4-arylphthalazines or analogues thereof, described inLucas B. S. et al., Bioorg. Med. Chem. Lett. 2010; 20(12):3618-22.

Other chemotherapeutic agents include, but are not limited to,anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRHagonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamideand bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA),phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A(2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide),platinum containing compounds (e.g. cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine,and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalentsuch as nanoparticle albumin-bound paclitaxel (Abraxane),docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxelbound to the erbB2-recognizing peptide EC-1), and glucose-conjugatedpaclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate,teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMPdehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin,and EICAR), ribonucleotide reductase inhibitors (e.g. hydroxyurea anddeferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine,doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosineanalogs (e.g. cytarabine (ara C), cytosine arabinoside, andfludarabine), purine analogs (e.g. mercaptopurine and Thioguanine),Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylationinhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g.1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.staurosporine), actinomycin (e.g. actinomycin D, dactinomycin),bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin),imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g.,axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™,AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®),gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib(TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272),nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®,SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474),vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab(AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab(VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib(NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumabozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765,AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523,PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/orXL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTORinhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus(RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235(Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502(Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)),oblimersen, gemcitabine, caminomycin, leucovorin, pemetrexed,cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, caminomycinaminopterin, and hexamethyl melamine.

Exemplary biotherapeutic agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immunostimulants and/or immuno-modulatory agents (e.g.,IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g. Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab),ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar(tositumomab)).

In some embodiments, the chemotherapeutic is selected from HSP90inhibitors. The HSP90 inhibitor can be a geldanamycin derivative, e.g.,a benzoquinone or hygroquinone ansamycin HSP90 inhibitor (e.g., IPI-493and/or IPI-504). Non-limiting examples of HSP90 inhibitors includeIPI-493, IPI-504, 17-AAG (also known as tanespimycin or CNF-1010),BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known as VER-49009),SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, 17-DMAG,CNF-1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159,CCT-129397, PU-H71, or PF-04928473 (SNX-2112).

In some embodiments, the chemotherapeutic is selected from PI3Kinhibitors (e.g., including those PI3K inhibitors provided herein andthose PI3K inhibitors not provided herein). In some embodiment, the PI3Kinhibitor is an inhibitor of delta and gamma isoforms of PI3K. In someembodiment, the PI3K inhibitor is an inhibitor of delta isoform of PI3K.In some embodiment, the PI3K inhibitor is an inhibitor of gamma isoformof PI3K. In some embodiments, the PI3K inhibitor is an inhibitor ofalpha isoform of PI3K. In other embodiments, the PI3K inhibitor is aninhibitor of one or more alpha, beta, delta and gamma isoforms of PI3K.Exemplary PI3K inhibitors that can be used in combination are describedin, e.g., WO 09/088,990, WO 09/088,086, WO 2011/008302, WO 2010/036380,WO 2010/006086, WO 09/114,870, WO 05/113556; US 2009/0312310, and US2011/0046165, each incorporated herein by reference. Additional PI3Kinhibitors that can be used in combination with the pharmaceuticalcompositions, include but are not limited to, AMG-319, GSK 2126458,GDC-0980, GDC-0941, Sanofi XL147, XL499, XL756, XL147, PF-4691502, BKM120, CAL-101 (GS-1101), CAL 263, SF1126, PX-886, and a dual PI3Kinhibitor (e.g., Novartis BEZ235). In one embodiment, the PI3K inhibitoris an isoquinolinone.

In some embodiments, provided herein is a method for using the acompound provided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, in combination withradiation therapy in inhibiting abnormal cell growth or treating thehyperproliferative disorder in the subject. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of acompound provided herein in this combination therapy can be determinedas described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation, external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner as provided herein include both solids and liquids. Byway of non-limiting example, the radiation source can be a radionuclide,such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solidsource, or other radionuclides that emit photons, beta particles, gammaradiation, or other therapeutic rays. The radioactive material can alsobe a fluid made from any solution of radionuclide(s), e.g., a solutionof I-125 or I-131, or a radioactive fluid can be produced using a slurryof a suitable fluid containing small particles of solid radionuclides,such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in agel or radioactive micro spheres.

Without being limited by any theory, a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or a pharmaceutical composition as providedherein, can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, provided herein is a method for sensitizing abnormalcells in a subject to treatment with radiation which comprisesadministering to the subject an amount of a compound provided herein, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, which amount is effective in sensitizing abnormalcells to treatment with radiation. The amount of the compound used inthis method can be determined according to the means for ascertainingeffective amounts of such compounds described herein.

In one embodiment, a compound as provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can be usedin combination with an amount of one or more substances selected fromanti-angiogenesis agents, signal transduction inhibitors, andantiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound provided herein, or a pharmaceutically acceptable form thereof,or a pharmaceutical composition described herein. Anti-angiogenesisagents include, for example, rapamycin, temsirolimus (CCI-779),everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples ofuseful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, androfecoxib. Examples of useful matrix metalloproteinase inhibitors aredescribed in WO 96/33172 (published Oct. 24, 1996), WO 96/27583(published Mar. 7, 1996), European Patent Application No. 97304971.1(filed Jul. 8, 1997), European Patent Application No. 99308617.2 (filedOct. 29, 1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516(published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998), WO98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug. 6,1998), WO 98/30566 (published Jul. 16, 1998), European PatentPublication 606,046 (published Jul. 13, 1994), European PatentPublication 931, 788 (published Jul. 28, 1999), WO 90/05719 (publishedMay 31, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCTInternational Application No. PCT/IB98/01113 (filed Jul. 21, 1998),European Patent Application No. 99302232.1 (filed Mar. 25, 1999), GreatBritain Patent Application No. 9912961.1 (filed Jun. 3, 1999), U.S.Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat.No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issuedJan. 19, 1999), and European Patent Publication 780,386 (published Jun.25, 1997), all of which are incorporated herein in their entireties byreference. In some embodiments, MMP-2 and MMP-9 inhibitors are thosethat have little or no activity inhibiting MMP-1. Other embodimentsinclude those that selectively inhibit MMP-2 and/or AMP-9 relative tothe other matrix-metalloproteinases (e.g., MAP-1, MMP-3, MMP-4, MMP-5,MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Somenon-limiting examples of MMP inhibitors are AG-3340, RO 32-3555, and RS13-0830.

Autophagy inhibitors include, but are not limited to, chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including, but not limited to ATG5 (which are implicated inautophagy), can also be used.

In some embodiments, provided herein is a method of and/or apharmaceutical composition for treating a cardiovascular disease in asubject which comprises an amount of a compound provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, and an amount of one or more therapeutic agentsuse for the treatment of cardiovascular diseases.

Exemplary agents for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, anti-proliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings. Moreover, a coating can be used to effect therapeutic deliveryfocally within the vessel wall. By incorporation of the active agent ina swellable polymer, the active agent will be released upon swelling ofthe polymer.

In one embodiment, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or a pharmaceutical composition as provided herein, can beformulated or administered in conjunction with liquid or solid tissuebarriers also known as lubricants. Examples of tissue barriers include,but are not limited to, polysaccharides, polyglycans, seprafilm,interceed and hyaluronic acid.

Medicaments which can be administered in conjunction with a compoundprovided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, include anysuitable drugs usefully delivered by inhalation for example, analgesics,e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine;anginal preparations, e.g., diltiazem; antiallergics, e.g. cromoglycate,ketotifen or nedocromil; anti-infectives, e.g., cephalosporins,penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. It will be clear to a personskilled in the art that, where appropriate, the medicaments can be usedin the form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) to optimize theactivity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude, but are not limited to, agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated herein include drugs used forcontrol of gastric acidity, agents for the treatment of peptic ulcers,agents for the treatment of gastroesophageal reflux disease, prokineticagents, antiemetics, agents used in irritable bowel syndrome, agentsused for diarrhea, agents used for constipation, agents used forinflammatory bowel disease, agents used for biliary disease, agents usedfor pancreatic disease. Therapeutic agents include, but are not limitedto, those used to treat protozoan infections, drugs used to treatMalaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, and/orLeishmaniasis, and/or drugs used in the chemotherapy of helminthiasis.Other therapeutic agents include, but are not limited to, antimicrobialagents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, andagents for urinary tract infections, penicillins, cephalosporins, andother, β-Lactam antibiotics, an agent containing an aminoglycoside,protein synthesis inhibitors, drugs used in the chemotherapy oftuberculosis, mycobacterium avium complex disease, and leprosy,antifungal agents, antiviral agents including nonretroviral agents andantiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundprovided herein include but are not limited to anti-receptor tyrosinekinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20antibodies (rituximab, tositumomab), and other antibodies such asalemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immuno-modulation, such asimmuno-modulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and anti-platelet drugs are alsocontemplated by the methods herein.

In exemplary embodiments, for treating renal carcinoma, one can combinea compound provided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, with sorafenib and/oravastin. For treating an endometrial disorder, one can combine acompound provided herein with doxorubincin, taxotere (taxol), and/orcisplatin (carboplatin). For treating ovarian cancer, one can combine acompound provided herein with cisplatin (carboplatin), taxotere,doxorubincin, topotecan, and/or tamoxifen. For treating breast cancer,one can combine a compound provided herein with taxotere (taxol),gemcitabine (capecitabine), tamoxifen, letrozole, tarceva, lapatinib,PD0325901, avastin, herceptin, OSI-906, and/or OSI-930. For treatinglung cancer, one can combine a compound as provided herein with taxotere(taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/oravastin.

In some embodiments, the disorder to be treated, prevented and/ormanaged is hematological cancer, e.g., lymphoma (e.g., T-cell lymphoma;NHL), myeloma (e.g., multiple myeloma), and leukemia (e.g., CLL), and acompound provided herein is used in combination with: HDAC inhibitorssuch as vorinostat and romidepsin; mTOR inhibitors such as everolmus;anti-folates such as pralatrexate; nitrogen mustard such asbendamustine; gemcitabine, optionally in further combination withoxaliplatin; rituximab-cyclophosphamide combination; PI3K inhibitorssuch as GS-1101, XL 499, GDC-0941, and AMG-319; or BTK inhibitors suchas ibrutinib and AVL-292.

In certain embodiments, wherein inflammation (e.g., arthritis, asthma)is treated, prevented and/or managed, a compound provided herein can becombined with, for example: PI3K inhibitors such as GS-1101, XL 499,GDC-0941, and AMG-319; BTK inhibitors such as ibrutinib and AVL-292; JAKinhibitors such as tofacitinib, fostamatinib, and GLPG0636.

In certain embodiments wherein asthma is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:beta 2-agonists such as, but not limited to, albuterol (Proventil®, orVentolin®), salmeterol (Serevent®), formoterol (Foradil®),metaproterenol (Alupent®), pirbuterol (MaxAir®), and terbutalinesulfate; corticosteroids such as, but not limited to, budesonide (e.g.,Pulmicort®), flunisolide (e.g., AeroBid Oral Aerosol Inhaler® orNasalide Nasal Aerosol®), fluticasone (e.g., Flonase® or Flovent®) andtriamcinolone (e.g., Azmacort®); mast cell stabilizers such as cromolynsodium (e.g., Intal® or Nasalcrom®) and nedocromil (e.g., Tilade®);xanthine derivatives such as, but not limited to, theophylline (e.g.,Aminophyllin®, Theo-24® or Theolair®); leukotriene receptor antagonistssuch as, but are not limited to, zafirlukast (Accolate®), montelukast(Singulair®), and zileuton (Zyflo®); and adrenergic agonists such as,but are not limited to, epinephrine (Adrenalin®, Bronitin®, EpiPen® orPrimatene Mist®).

In certain embodiments wherein arthritis is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:TNF antagonist (e.g., a TNF antibody or fragment, a soluble TNF receptoror fragment, fusion proteins thereof, or a small molecule TNFantagonist); an anti-rheumatic (e.g., methotrexate, auranofin,aurothioglucose, azathioprine, etanercept, gold sodium thiomalate,hydroxychloroquine sulfate, leflunomide, sulfasalzine); a musclerelaxant; a narcotic; a non-steroid anti-inflammatory drug (NSAID); ananalgesic; an anesthetic; a sedative; a local anesthetic; aneuromuscular blocker; an antimicrobial (e.g., an aminoglycoside, anantifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin,a fluoroquinolone, a macrolide, a penicillin, a sulfonamide, atetracycline, another antimicrobial); an antipsoriatic; acorticosteroid; an anabolic steroid; a cytokine or a cytokineantagonist.

In certain embodiments wherein psoriasis is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:budesonide, epidermal growth factor, corticosteroids, cyclosporine,sulfasalazine, aminosalicylates, 6-mercaptopurine, azathioprine,metronidazole, lipoxygenase inhibitors, mesalamine, olsalazine,balsalazide, antioxidants, thromboxane inhibitors, IL-1 receptorantagonists, anti-IL-1β monoclonal antibodies, anti-IL-6 monoclonalantibodies, growth factors, elastase inhibitors, pyridinyl-imidazolecompounds, antibodies or agonists of TNF, LT, IL-1, IL-2, IL-6, IL-7,IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF, antibodies ofCD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or theirligands, methotrexate, cyclosporine, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids, prednisolone,phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents,complement inhibitors, adrenergic agents, IRAK, NIK, IKK, p38, MAPkinase inhibitors, IL-1β converting enzyme inhibitors, TNFα convertingenzyme inhibitors, T-cell signaling inhibitors, metalloproteinaseinhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensinconverting enzyme inhibitors, soluble cytokine receptors, soluble p55TNF receptor, soluble p75 TNF receptor, sIL-1RI, sIL-1RII, sIL-6R,anti-inflammatory cytokines, IL-4, IL-10, IL-11, IL-13 and TGFβ.

In certain embodiments wherein fibrosis or fibrotic condition of thebone marrow is treated, prevented and/or managed, a compound providedherein can be combined with, for example, a Jak2 inhibitor (including,but not limited to, INCB018424, XL019, TG101348, or TG101209), animmuno-modulator, e.g., an IMID® (including, but not limited tothalidomide, lenalidomide, or panolinomide), hydroxyurea, an androgen,erythropoietic stimulating agents, prednisone, danazol, HDAC inhibitors,or other agents or therapeutic modalities (e.g., stem cell transplants,or radiation).

In certain embodiments wherein fibrosis or fibrotic condition of theheart is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, eplerenone, furosemide, pycnogenol,spironolactone, TcNC100692, torasemide (e.g., prolonged release form oftorasemide), or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thekidney is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, cyclosporine, cyclosporine A,daclizumab, everolimus, gadofoveset trisodium (ABLAVAR®), imatinibmesylate (GLEEVEC®), matinib mesylate, methotrexate, mycophenolatemofetil, prednisone, sirolimus, spironolactone, STX-100, tamoxifen,TheraCLEC™, or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of theskin is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, Bosentan (Tracleer), p144,pentoxifylline; pirfenidone; pravastatin, STI571, Vitamin E, orcombinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thegastrointestinal system is treated, prevented and/or managed, a compoundprovided herein can be combined with, for example, ALTU-135, bucelipasealfa (INN), DCI1020, EUR-1008 (ZENPEP™), ibuprofen, Lym-X-Sorb powder,pancrease MT, pancrelipase (e.g., pancrelipase delayed release), pentadecanoic acid (PA), repaglinide, TheraCLEC™, triheptadecanoin (THA),ULTRASE MT20, ursodiol, or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thelung is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, 18-FDG, AB0024, ACT-064992(macitentan), aerosol interferon-gamma, aerosolized human plasma-derivedalpha-1 antitrypsin, alpha1-proteinase inhibitor, ambrisentan, amikacin,amiloride, amitriptyline, anti-pseudomonas IgY gargle, ARIKACE™,AUREXIS® (tefibazumab), AZAPRED, azathioprine, azithromycin,azithromycin, AZLI, aztreonam lysine, BIBF1120, Bio-25 probiotic,bosentan, Bramitob®, calfactant aerosol, captopril, CC-930, ceftazidime,ceftazidime, cholecalciferol (Vitamin D3), ciprofloxacin (CIPRO®,BAYQ3939), CNTO 888, colistin CF, combined Plasma Exchange (PEX),rituximab, and corticosteroids, cyclophosphamide, dapsone, dasatinib,denufosol tetrasodium (INS37217), dornase alfa (PULMOZYME®), EPI-hNE4,erythromycin, etanercept, FG-3019, fluticasone, FTI, GC1008, GS-9411,hypertonic saline, ibuprofen, iloprost inhalation, imatinib mesylate(GLEEVEC®), inhaled sodium bicarbonate, inhaled sodium pyruvate,interferon gamma-1b, interferon-alpha lozenges, isotonic saline, IW001,KB001, losartan, lucinactant, mannitol, meropenem, meropenem infusion,miglustat, minocycline, Moli1901, MP-376 (levofloxacin solution forinhalation), mucoid exopolysaccharide P. aeruginosa immune globulin IV,mycophenolate mofetil, n-acetylcysteine, N-acetylcysteine (NAC), NaCl6%, nitric oxide for inhalation, obramycin, octreotide, oligoG CF-5/20,Omalizumab, pioglitazone, piperacillin-tazobactam, pirfenidone,pomalidomide (CC-4047), prednisone, prevastatin, PRM-151, QAX576,rhDNAse, SB656933, SB-656933-AAA, sildenafil, tamoxifen, technetium[Tc-99 m] sulfur colloid and Indium [In-111] DTPA, tetrathiomolybdate,thalidomide, ticarcillin-clavulanate, tiotropium bromide, tiotropiumRESPIMAT® inhaler, tobramycin (GERNEBCIN®), treprostinil, uridine,valganciclovir (VALCYTE®), vardenafil, vitamin D3, xylitol, zileuton, orcombinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of theliver is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, adefovir dipivoxil, candesartan,colchicine, combined ATG, mycophenolate mofetil, and tacrolimus,combined cyclosporine microemulsion and tacrolimus, elastometry,everolimus, FG-3019, Fuzheng Huayu, GI262570, glycyrrhizin (monoammoniumglycyrrhizinate, glycine, L-cysteine monohydrochloride), interferongamma-1b, irbesartan, losartan, oltipraz, ORAL IMPACT®, peginterferonalfa-2a, combined peginterferon alfa-2a and ribavirin, peginterferonalfa-2b (SCH 54031), combined peginterferon alpha-2b and ribavirin,praziquantel, prazosin, raltegravir, ribavirin (REBETOL®, SCH 18908),ritonavir-boosted protease inhibitor, pentoxyphilline, tacrolimus,tauroursodeoxycholic acid, tocopherol, ursodiol, warfarin, orcombinations thereof.

In certain embodiments wherein cystic fibrosis is treated, preventedand/or managed, a compound provided herein can be combined with, forexample, 552-02, 5-methyltetrahydrofolate and vitamin B12, Ad5-CB-CFTR,Adeno-associated virus-CFTR vector, albuterol, alendronate, alphatocopherol plus ascorbic acid, amiloride HCl, aquADEK™, ataluren(PTC124), AZD1236, AZD9668, azithromycin, bevacizumab, biaxin(clarithromycin), BIIL 283 BS (amelubent), buprofen, calcium carbonate,ceftazidime, cholecalciferol, choline supplementation, CPX, cysticfibrosis transmembrane conductance regulator, DHA-rich supplement,digitoxin, cocosahexaenoic acid (DHA), doxycycline, ECGC, ecombinanthuman IGF-1, educed glutathione sodium salt, ergocalciferol (vitaminD2), fluorometholone, gadobutrol (GADOVIST®, BAY86-4875), gentamicin,ghrelin, glargine, glutamine, growth hormone, GS-9411, H5.001CBCFTR,human recombinant growth hormone, hydroxychloroquine, hyperbaric oxygen,hypertonic saline, IH636 grape seed proanthocyanidin extract, insulin,interferon gamma-1b, IoGen (molecular iodine), iosartan potassium,isotonic saline, itraconazole, IV gallium nitrate (GANITE®) infusion,ketorolac acetate, lansoprazole, L-arginine, linezolid, lubiprostone,meropenem, miglustat, MP-376 (levofloxacin solution for inhalation),normal saline IV, Nutropin AQ, omega-3 triglycerides, pGM169/GL67A,pGT-1 gene lipid complex, pioglitazone, PTC124, QAU145, salmeterol,SB656933, SB656933, simvastatin, sitagliptin, sodium 4-phenylbutyrate,standardized turmeric root extract, tgAAVCF, TNF blocker, TOBI,tobramycin, tocotrienol, unconjugated Isoflavones 100, vitamin: cholinebitartrate (2-hydroxyethyl) trimethylammonium salt 1:1, VX-770, VX-809,Zinc acetate, or combinations thereof.

In some embodiments, a compound provided herein is administered incombination with an agent that inhibits IgE production or activity. Insome embodiments, the PI3K inhibitor (e.g., PI3Kδ inhibitor) isadministered in combination with an inhibitor of mTOR. Agents thatinhibit IgE production are known in the art and they include but are notlimited to one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

In certain embodiments wherein scleroderma is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:an immunosuppressant (e.g., methotrexate, azathioprine (Imuran®),cyclosporine, mycophenolate mofetil (Cellcept®), and cyclophosphamide(Cytoxan®)); T-cell-directed therapy (e.g., halofuginone, basiliximab,alemtuzumab, abatacept, rapamycin); B-cell directed therapy (e.g.,rituximab); autologous hematopoietic stem cell transplantation; achemokine ligand receptor antagonist (e.g., an agent that targets theCXCL12/CSCR4 axis (e.g., AMD3100)); a DNA methylation inhibitor (e.g.,5-azacytidine); a histone deacetylase inhibitor (e.g., trichostatin A);a statin (e.g., atorvastatin, simvastatin, pravastatin); an endothelinreceptor antagonist (e.g., Bosentan®); a phosphodiesterase type Vinhibitor (e.g., Sildenafil®); a prostacyclin analog (e.g.,trepostinil); an inhibitor of cytokine synthesis and/or signaling (e.g.,Imatinib mesylate, Rosiglitazone, rapamycin, antitransforming growthfactor β1 (anti-TGFβ1) antibody, mycophenolate mofetil, an anti-IL-6antibody (e.g., tocilizumab)); corticosteroids; nonsteroidalanti-inflammatory drugs; light therapy; and blood pressure medications(e.g., ACE inhibitors).

In certain embodiments wherein inflammatory myopathies are treated,prevented and/or managed, a compound provided herein can be combinedwith, for example: topical creams or ointments (e.g., topicalcorticosteroids, tacrolimus, pimecrolimus); cyclosporine (e.g., topicalcyclosporine); an anti-interferon therapy, e.g., AGS-009, Rontalizumab(rhuMAb IFNalpha), Vitamin D3, Sifalimumab (MEDI-545), AMG 811, IFNαKinoid, or CEP33457. In some embodiments, the other therapy is an IFN-αtherapy, e.g., AGS-009, Rontalizumab, Vitamin D3, Sifalimumab (MEDI-545)or IFNα Kinoid; corticosteroids such as prednisone (e.g., oralprednisone); immunosuppressive therapies such as methotrexate (Trexall®,Methotrexate®, Rheumatrex®), azathioprine (Azasan®, Imuran®),intravenous immunoglobulin, tacrolimus (Prograf®), pimecrolimus,cyclophosphamide (Cytoxan®), and cyclosporine (Gengraf®, Neoral®,Sandimmune®); anti-malarial agents such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®); total body irradiation;rituximab (Rituxan®); TNF inhibitors (e.g., etanercept (Enbrel®),infliximab (Remicade®)); AGS-009; Rontalizumab (rhuMAb IFNalpha);Vitamin D3; Sifalimumab (MEDI-545); AMG 811; IFNα Kinoid; CEP33457;agents that inhibit IgE production such as TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2;agents that inhibit IgE activity such as anti-IgE antibodies (e.g.,Omalizumab and TNX-90); and additional therapies such as physicaltherapy, exercise, rest, speech therapy, sun avoidance, heat therapy,and surgery.

In certain embodiments wherein myositis (e.g., dermatomysitis) istreated, prevented and/or managed, a compound provided herein can becombined with, for example: corticosteroids; corticosteroid sparingagents such as, but not limited to, azathioprine and methotrexate;intravenous immunoglobulin; immunosuppressive agents such as, but notlimited to, tacrolimus, cyclophosphamide and cyclosporine; rituximab;TNFα inhibitors such as, but not limited to, etanercept and infliximab;growth hormone; growth hormone secretagogues such as, but not limitedto, MK-0677, L-162752, L-163022, NN703 ipamorelin, hexarelin, GPA-748(KP102, GHRP-2), and LY444711 (Eli Lilly); other growth hormone releasestimulators such as, but not limited to, Geref, GHRH (1-44), Somatorelin(GRF 1-44), ThGRF genotropin, L-DOPA, glucagon, and vasopressin; andinsulin-like growth factor.

In certain embodiments wherein Sjögren's syndrome is treated, preventedand/or managed, a compound provided herein can be combined with, forexample: pilocarpine; cevimeline; nonsteroidal anti-inflammatory drugs;arthritis medications; antifungal agents; cyclosporine;hydroxychloroquine; prednisone; azathioprine; and cyclophamide.

Further therapeutic agents that can be combined with a compound providedherein can be found in Goodman and Gilman's “The Pharmacological Basisof Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman orthe Physician's Desk Reference, both of which are incorporated herein byreference in their entirety.

In one embodiment, the compounds described herein can be used incombination with the agents provided herein or other suitable agents,depending on the condition being treated. Hence, in some embodiments, acompound provided herein, or a pharmaceutically acceptable form thereof,will be co-administered with other agents as described above. When usedin combination therapy, a compound described herein, or apharmaceutically acceptable form thereof, can be administered with asecond agent simultaneously or separately. This administration incombination can include simultaneous administration of the two agents inthe same dosage form, simultaneous administration in separate dosageforms, and separate administration. That is, a compound described hereinand any of the agents described above can be formulated together in thesame dosage form and administered simultaneously. Alternatively, acompound provided herein and any of the agents described above can besimultaneously administered, wherein both agents are present in separateformulations. In another alternative, a compound provided herein can beadministered just followed by any of the agents described above, or viceversa. In the separate administration protocol, a compound providedherein and any of the agents described above can be administered a fewminutes apart, or a few hours apart, or a few days apart.

Administration of a compound provided herein, or a pharmaceuticallyacceptable form thereof, can be effected by any method that enablesdelivery of the compound to the site of action. An effective amount of acompound provided herein, or a pharmaceutically acceptable form thereof,can be administered in either single or multiple doses by any of theaccepted modes of administration of agents having similar utilities,including rectal, buccal, intranasal, and transdermal routes, byintra-arterial injection, intravenously, intraperitoneally,parenterally, intramuscularly, subcutaneously, orally, topically, as aninhalant, or via an impregnated or coated device such as a stent, forexample, or an artery-inserted cylindrical polymer.

When a compound provided herein, or a pharmaceutically acceptable formthereof, is administered in a pharmaceutical composition that comprisesone or more agents, and the agent has a shorter half-life than thecompound provided herein, unit dose forms of the agent and the compoundas provided herein can be adjusted accordingly.

The examples and preparations provided below further illustrate andexemplify the compounds as provided herein and methods of preparing suchcompounds. It is to be understood that the scope of the presentdisclosure is not limited in any way by the scope of the followingexamples and preparations. In the following examples molecules with asingle chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers can be obtained by methods known to thoseskilled in the art.

EXAMPLES Chemical Examples

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques well known inthe art.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period that is, for example, about 1 to about24 hours; reactions left to run overnight in some embodiments canaverage a period of about 16 hours.

The terms “solvent,” “organic solvent,” and “inert solvent” each mean asolvent inert under the conditions of the reaction being described inconjunction therewith including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, N-methylpyrrolidone (“NMP”), pyridine, and the like. Unlessspecified to the contrary, the solvents used in the reactions describedherein are inert organic solvents. Unless specified to the contrary, foreach gram of the limiting reagent, one cc (or mL) of solvent constitutesa volume equivalent.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure, such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography, orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation proceduresare given by reference to the examples herein below. However, otherequivalent separation or isolation procedures can also be used.

When desired, the (R)- and (S)-isomers of the non-limiting exemplarycompounds, if present, can be resolved by methods known to those skilledin the art, for example by formation of diastereoisomeric salts orcomplexes which can be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which can be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a specific enantiomer can besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer tothe other by asymmetric transformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In some embodiments, compounds provided herein can generally besynthesized by an appropriate combination of generally well knownsynthetic methods. Techniques useful in synthesizing these chemicalentities are both readily apparent and accessible to those of skill inthe relevant art, based on the instant disclosure. Many of theoptionally substituted starting compounds and other reactants arecommercially available, e.g., from Aldrich Chemical Company (Milwaukee,Wis.) or can be readily prepared by those skilled in the art usingcommonly employed synthetic methodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in making the compounds and is not intended tolimit the scope of reactions or reaction sequences that can be used inpreparing the compounds provided herein.

General Synthetic Methods

The compounds herein being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodiments,and are not intended to limit these aspects and embodiments.

(i) General Method for the Synthesis of Amine Cores:

General conditions for the preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones:

To a stirred mixture of a given o-methylbenzoic acid (A-1) (1.5 mol, 1eq) and DMF (2 mL) in DCM (1275 mL) at RT, oxalyl chloride (1.65 mol,1.1 eq) is added over 5 min and the resulting mixture is stirred at RTfor 2 h. The mixture is then concentrated in vacuo. The residue isdissolved in DCM (150 mL) and the resulting solution (solution A) isused directly in the next step.

To a stirred mixture of aniline (1.58 mol, 1.05 eq) and triethylamine(3.15 mol, 2.1 eq) in DCM (1350 mL), the above solution A (150 mL) isadded dropwise while the reaction temperature is maintained between 25°C. to 40° C. by an ice-water bath. The resulting mixture is stirred atRT for 2 h and then water (1000 mL) is added. The organic layers areseparated and washed with water (2×1000 mL), dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo. The product issuspended in n-heptanes (1000 mL) and stirred at RT for 30 min. Theprecipitate is collected by filtration, rinsed with heptanes (500 mL)and further dried in vacuo to afford the amide (A-2).

To a stirred mixture of amide (A-2) (173 mmol, 1 eq) in anhydrous THF(250 mL) at −30° C. under an argon atmosphere, a solution ofn-butyllithium in hexanes (432 mol, 2.5 eq) is added dropwise over 30min while keeping the inner temperature between −30° C. and −10° C. Theresulting mixture is then stirred at −30° C. for 30 min.

To a stirred mixture of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (260 mmol, 1.5 eq) inanhydrous THF (250 mL) at −30° C. under an argon atmosphere, a solutionof isopropylmagnesium chloride in THF (286 mmol, 1.65 eq) is addeddropwise over 30 min while keeping inner temperature between −30° C. and−10° C. The resulting mixture is stirred at −30° C. for 30 min. Thissolution is then slowly added to above reaction mixture while keepinginner temperature between −30° C. and −10° C. The resulting mixture isstirred at −15° C. for 1 h. The reaction mixture is quenched with water(50 mL) and then acidified with conc. HCl at −10° C. to 0° C. to adjustthe pH to 1-3. The mixture is allowed to warm to RT and concentrated invacuo. The residue is dissolved in MeOH (480 mL), and then conc. HCl(240 mL) is added quickly at RT. The resulting mixture is stirred atreflux for 1 h. The reaction mixture is concentrated in vacuo to reducethe volume to about 450 mL. The residue is extracted with a 2:1 mixtureof heptane and ethyl acetate (2×500 mL). The aqueous layer is basifiedwith concentrated ammonium hydroxide to adjust the pH value to 9-10while keeping the inner temperature between −10° C. and 0° C. Themixture is then extracted with DCM (3×300 mL), washed with brine, driedover MgSO₄ and filtered. The filtrate is concentrated in vacuo and theresidue is dissolved in MeOH (1200 mL) at RT. To this solution,D-(−)-tartaric acid (21 g, 140 mmol, 0.8 eq) is added in one portion atRT. After stirring at RT for 30 min, a white solid precipitates and themixture is slurried at RT for 10 h. The solid is collected by filtrationand rinsed with MeOH (3×50 mL). The collected solid is suspended inwater (500 mL) and then neutralized with concentrated ammonium hydroxidesolution at RT to adjust the pH to 9-10. The mixture is extracted withDCM (3×200 mL). The combined organic layers are washed with brine, driedover MgSO₄ and filtered. The filtrate is concentrated in vacuo to affordthe (S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones (A-3).

General conditions for the preparation of3-(aminomethyl)-isoquinolin-1(2H)-ones

A mixture of benzoic acid (B-1) (400 mmol), oxalyl chloride (101 g, 800mmol) and DMF (0.2 ml) in DCM (400 mL) is stirred at RT for 2 h. Themixture is concentrated in vacuo to afford the acid chloride (B-2). Theproduct obtained is used directly in the next step without furtherpurification.

A mixture of R₂NH₂ amine (420 mmol) and triethylamine (700 mmol) in DCM(300 mL) is stirred at RT for 10 min. To this mixture, acid chloride(B-2) (400 mmol) is added dropwise, and the resulting mixture is stirredat RT for 30 min. The reaction mixture is poured into water (300 mL) andextracted with DCM (3×200 mL), dried over anhydrous Na₂SO₄ and filtered.The filtrate is concentrated in vacuo to afford the product. The productis suspended in isopropyl ether (300 mL), stirred at reflux for 30 min,and then cooled to 0-5° C. The precipitate is collected by filtrationand further dried in vacuo to afford the product amide (B-3).

To a stirred solution of amide (B-3) (0.1 mol, 1.0 eq) in anhydrous THF(225 mL) at −78° C. under an argon atmosphere, a solution ofn-butyllithium in hexanes (120 mL, 2.5 M, 0.3 mol, 3 eq) is addeddropwise over 1 h period of time while keeping inner temperature between−78° C. to −50° C. The resulting mixture is stirred at −70° C. for 1 h,and then diethyl oxalate (17.5 g, 0.12 mol, 1.2 eq) is quickly added(with an increase in temperature to −20° C. upon addition). The mixtureis stirred at −50° C. for 10 min, and then quenched with water (100 mL).The inorganic salt is removed by filtration, and the filtrate is washedwith ethyl acetate (2×100 mL). The combined organic layers are washedwith brine (100 mL), dried over MgSO₄ and filtered. The filtrate isconcentrated in vacuo to afford the product as a semi-solid. The productis slurried in isopropyl ether (100 mL) at RT for 10 min. The solid iscollected by filtration and further dried in vacuo to afford the product(B-4). The product obtained is used directly in the next step.

Compound (B-4) (88 mmol, 1 eq) is dissolved in HCl/MeOH (10 M, 100 mL),and the resulting mixture is stirred at reflux for 1 h. The reactionmixture is concentrated in vacuo, and the residue is slurried in ethylacetate (100 mL) at RT for 30 min. The solid is collected by filtration,rinsed with ethyl acetate (3×50 mL), and further dried in vacuo toafford the product (B-5).

To a stirred suspension of lithium aluminum hydride (15.6 g, 410 mmol)in anhydrous THF (500 mL) at −78° C. under a nitrogen atmosphere, (B-5)(137 mmol) is slowly added over a 10 min period of time. The resultingmixture is allowed to warm to −30° C. and stirred for 30 min. Themixture is then cooled to −78° C., and quenched carefully with water(100 mL). The mixture is allowed to warm to RT, filtered through silicagel (20 g), and the filtrate is concentrated in vacuo. The productmixture is poured into H₂O (200 mL) and extracted with ethyl acetate(3×200 mL). The combined organic layers are washed with brine (100 mL),dried over Na₂SO₄ and filtered. The filtrate is concentrated in vacuo.The product is suspended in ethyl acetate (30 mL) and stirred for 10min. The solid is collected by filtration and further dried in vacuo toafford the product (B-6).

Phosphorus tribromide (3.42 g, 12.6 mmol, 1.2 eq) and DMF (1.6 g, 21.0mmol, 2.0 eq) is dissolved in CH₃CN (100 mL) and the resulting mixtureis stirred at −10° C. for 10 min. To this mixture, alcohol (B-6) (10.5mmol, 1.0 eq) is added in portions. The resulting mixture is allowed towarm to RT and stirred for an additional 30 min. The reaction mixture isneutralized with saturated aqueous NaHCO₃ solution at 0-5° C. and thenfiltered. The filtrate is extracted with ethyl acetate (3×100 mL). Thecombined organic layers are washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo and the residue ispurified by flash column chromatography on silica gel (20% ethylacetate-petroleum ether) to afford the product bromide (B-7).

To a stirred mixture of phthalimide (6.93 mmol, 1.1 eq) in DMF (20 mL)at RT, potassium-tert-butoxide (1.1 g, 9.45 mmol, 1.5 eq) is added inportions over 10 min and then bromide (B-7) (6.3 mmol, 1.0 eq) is added.The resulting mixture is stirred at 100° C. for 2 h. The reactionmixture is allowed to cool to RT and then poured into ice-water (30 mL).The mixture is extracted with ethyl acetate (3×20 mL). The combinedorganic layers are washed with brine, dried over Na₂SO₄ and filtered.The filtrate is concentrated in vacuo and the residue is purified byflash column chromatography on silica gel (16% ethyl acetate-petroleumether) to afford the product dione (B-8).

Dione (B-8) (1.5 mmol, 1.0 eq) and hydrazine hydrate (600 mg, 12 mmol,8.0 eq) are dissolved in EtOH (20 mL) and the resulting mixture isstirred at reflux for 1 h. The mixture is allowed to cool to RT and thenfiltered. The filter cake is washed with EtOH (10 mL). The combinedfiltrate is concentrated in vacuo and the residue is purified by flashcolumn chromatography on silica gel (2.5% MeOH-DCM) to afford the amine(B-9).

General conditions for the preparation of6-(1-aminoethyl)-3-methyl-isothiazolo[4,5-c]pyridin-4(5H)-ones

To a solution of methyl 3-aminocrotonate (C-1) (10.0 g. 86.9 mmol) inanhydrous THF (200 mL) at 0° C., a solution of phosphoryl chloride (12.0mL, 95.6 mmol) in anhydrous DMF (28 mL) is added dropwise (over 10 min).The resulting mixture is stirred at 0° C. for 1 h and then stirred at30° C. for 4 h. The mixture is allowed to stand overnight in arefrigerator. Chilled ether (800 mL) is added to the reaction mixtureuntil a semi clear/oil residue is formed. The yellow ether layer isdecanted. The oil residue is then dissolved in DCM (500 mL) and washedwith NaHS aqueous solution (2.0 M). The organic layer is washed with H₂O(4×500 mL), dried over Na₂SO₄ and filtered. The filtrate is concentratedin vacuo to afford the product, methyl 3-amino-2-thioformylbut-2-enoate(C-2).

To a solution of methyl 3-amino-2-thioformylbut-2-enoate (C-2) (5.34 g,33.5 mmol) in EtOH (250 mL), a solution of meta-chloroperoxybenzoic acid(70-75%, 12.4 g, 50.3 mmol) in EtOH (150 mL) is added and the resultingmixture is stirred at reflux for 3 h. The mixture is allowed to cool toRT, quenched with saturated aqueous NaOH solution and then extractedwith ethyl acetate (2×200 mL). The combined organic layers are washedwith brine, dried over Na₂SO₄ and filtered. The filtrate is concentratedin vacuo to afford the product, 3-methylisothiazole-4-carboxylate (C-3).

To a solution of 3-methylisothiazole-4-carboxylate (C-3) (4.73 g, 30.1mmol) in THF-MeOH—H₂O (2:1:1, 50 mL), NaOH (3.61 g, 90.3 mmol) is addedand the resulting mixture is stirred at 40° C. for 16 h. The mixture isallowed to cool to RT and then acidified with concentrated HCl to adjustthe pH to 2-3. The precipitate is collected by filtration, rinsed withwater and dried in vacuo to afford the product,3-methylisothiazole-4-carboxylic acid (C-4).

To a solution of 3-methylisothiazole-4-carboxylic acid (C-4) (3.9 g,27.3 mmol) in anhydrous THF (150 mL) at −78° C. under argon, n-butyllithium solution (27.3 mL, 68.3 mmol) is added dropwise and theresulting mixture is stirred at −78° C. for 1 h. To this mixture, asolution of iodine (13.9 g, 54.6 mmol) in THF (50 mL) is added slowlyand the resulting mixture is stirred at RT for 1 h. The mixture isacidified with concentrated HCl to adjust the pH to 3-4, and thenextracted with ethyl acetate. The organic layer is washed with aqueousNa₂SO₃ solution. The aqueous layer is extracted with ethyl acetate. Thecombined organic layers are washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo to afford the product,5-iodo-3-methylisothiazole-4-carboxylic acid (C-5).

To a solution of 5-iodo-3-methylisothiazole-4-carboxylic acid (C-5)(4.45 g, 16.5 mmol) and DMF (3 drops) in anhydrous DCM (60 mL), oxalylchloride solution (2.0 M in DCM, 16.5 mL, 33.1 mmol) is added dropwiseand the resulting mixture is stirred at RT for 2 h. The reaction mixtureis concentrated in vacuo to afford the acyl chloride intermediate as anoil. The intermediate is dissolved in anhydrous THF (100 mL). To thismixture, amine R₂NH₂ (24.8 mmol) and N,N-diisopropylethylamine (4.09 mL,24.8 mmol) are added dropwise. The resulting mixture is stirred at RTfor 1 h. The reaction mixture is quenched with water and extracted withethyl acetate. The combined organic layers are washed with brine, driedover Na₂SO₄ and filtered. The filtrate is concentrated in vacuo toafford the amide (C-6).

To a solution of amide (C-6) (18.6 mmol) and tributyl(vinyl)tin (8.19mL, 27.9 mmol) in DMF (30 mL) under argon, Pd(PPh₃)₄ (1.07 g, 0.93 mmol)is added. The resulting mixture is stirred at 90° C. for 2 h. Themixture is allowed to cool to RT, quenched with water and extracted withethyl acetate (2×300 mL). The combined organic layers are washed withbrine, dried over Na₂SO₄ and filtered. The filtrate is concentrated invacuo and the residue is purified by flash column chromatography onsilica gel (0-25% ethyl acetate-hexanes) to afford the productcarboxamide (C-7).

To a solution of carboxamide (C-7) in anhydrous DMF (70 mL) at RT,sodium hydride (60% in mineral oil, 1.52 g, 37.9 mmol) is added inportions and the resulting mixture is stirred at RT for 45 min. To thismixture, ethyl chloroacetate (4.73 mL, 44.2 mmol) is added dropwise andthe resulting mixture is stirred for 2 h. The reaction mixture isquenched with water and extracted with ethyl acetate. The combinedorganic layers are washed with brine, dried over Na₂SO₄ and filtered.The filtrate is concentrated in vacuo to afford the acetate (C-8). Theproduct obtained is used in the next step without purification.

To a solution of acetate (C-8) (12.62 mmol) in 1,4-dioxane-H₂O (3:1, 100mL) at RT, osmium tetraoxide (4% wt in H₂O, 1.0 mL, 0.13 mmol) is addedand the resulting mixture is stirred for 30 min. To this mixture, sodiumperiodate (5.40 g, 25.24 mmol) is added and the resulting mixture isstirred at RT for 3 h. The mixture is filtered through celite and thefiltrate is extracted with ethyl acetate (2×100 mL). The combinedorganic layers are washed with brine, dried over Na₂SO₄ and filtered.The filtrate is concentrated in vacuo to afford the product acetate(C-9). The product obtained is used in the next step withoutpurification.

To a solution of acetate (C-9) (12.68 mmol) in a mixture of EtOH andethyl acetate (3:1, 200 mL), cesium carbonate (4.55 g, 13.95 mmol) isadded and the resulting mixture is stirred at 50° C. for 2 h. Themixture is allowed to cool to RT and concentrated in vacuo. The residueis partitioned between water and ethyl acetate. The organic layer iswashed with brine, dried over Na₂SO₄ and filtered. The filtrate isconcentrated in vacuo and the residue is purified by flash columnchromatography on silica gel (0-40% ethyl acetate-hexanes) to afford thecarboxylate (C-10).

To a solution of carboxylate (C-10) (2.48 mmol) in anhydrous MeOH (15mL), NaBH₄ (936 mg, 24.75 mmol) is added in portions and the resultingmixture is stirred at RT for 16 h. The mixture is partitioned betweenwater and ethyl acetate. The organic layer is washed with brine, driedover Na₂SO₄ and filtered. The filtrate is concentrated in vacuo toafford pyridin-4(5H)-one (C-11).

To a solution pyridin-4(5H)-one (C-11) (5.21 mmol) in anhydrous DCM (100mL), 4 Å molecular sieves (powder, 2.84 G), NMO(N-methylmorpholine-N-oxide) (1.22 g, 10.43 mmol) and TPAP(tetrapropylammonium perruthenate) (92 mg, 0.26 mmol) are addedsequentially. The resulting mixture is stirred at RT for 1 h and thenfiltered through a celite/silica gel pad. The filtrate is concentratedin vacuo to afford aldehyde (C-12).

To a solution of aldehyde (C-12) (3.90 mmol) in anhydrous THF (100 mL)at −78° C. under argon, methylmagnesium chloride solution (3.0 M in THF,3.25 mL, 9.754 mmol) is added dropwise and the resulting mixture isstirred from −78° C. to RT for 2 h. The mixture is quenched with water(50 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layers are washed with brine, dried over Na₂SO₄ and filtered.The filtrate is concentrated in vacuo to afford pyridin-4(5H)-one(C-13).

To a solution of pyridin-4(5H)-one (C-13) (0.48 mmol) in anhydrous THF(8 mL) at 0° C. under argon, triphenyl phosphine (230 mg, 0.88 mmol) isadded and the resulting mixture is stirred for 5 min. To this mixture,diphenyl phosphoryl azide (0.24 mL, 1.12 mmol) is added followed by slowaddition of diisopropyl azodicarboxylate (0.17 mL, 0.88 mmol) over 20min period of time. The resulting mixture is stirred from 0° C. to RTfor 2 h. The mixture is then partitioned between ethyl acetate andwater. The organic layer is washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo and the residue ispurified by ISCO (silica gel cartridge, 0-50% ethyl acetate-hexanes) toafford the azide (C-14).

A mixture of azide (C-14) (0.2489 mmol) and palladium (10% weight oncarbon, 23 mg, 20% of starting material by weight) in anhydrous MeOH (5mL) is degassed and flushed with hydrogen (three cycles). The reactionmixture is stirred under a hydrogen atmosphere (hydrogen balloon) at RTfor 1 h. The mixture is filtered through celite and rinsed with ethylacetate. The filtrate is concentrated in vacuo to afford the amine(C-15).

(ii) General Methods for Amide Synthesis:

To a mixture of amine (D-1) (0.5 mmol, 1.0 eq), W_(d)—COOH carboxylicacid (0.55 mmol, 1.1 eq), and N,N-diisopropylethylamine (0.17 mL, 1.0mmol, 2.0 eq) in anhydrous DMF (5 mL), 1-hydroxybenzotriazole hydrate(0.65 mmol, 1.3 eq) and EDC hydrochloride (0.65 mmol, 1.3 eq) are addedsequentially and the resulting mixture is stirred at RT for 2-16 h.Ice-water or saturated sodium carbonate solution is added to thereaction mixture and then stirred for 10 min. The precipitate iscollected by filtration, rinsed with water and dried in vacuo. The solidcollected is further purified by flash column chromatography on silicagel (0-10% MeOH-DCM) to afford the product amide (D-2).

Method E

A solution of amine (D-1) (0.25 mmol, 1 eq), W_(d)—COOH carboxylic acid(1.1 eq), and 1-hydroxybenzotriazole hydrate (1.3 eq) indimethylformamide (0.1 M) is treated with diisopropylethylamine (2 eq)and then EDC hydrochloride (63 mg, 1.3 eq). The reaction mixture isstirred at ambient temperature overnight. The reaction mixture isdiluted with water (5× solvent) and acetic acid (1.5 eq) is added, thenthe mixture is stirred in an ice bath for 40 min. The resultingprecipitate is collected by filtration, and washed with water (3×3 mL).The collected solid is dried in vacuo to afford amide (D-2).

To a stirred mixture of nitrobenzoic acid (F-1) (1.0 mol, 1.0 eq) andDMF (2.0 mL) in toluene (800 mL), thionyl chloride (292 mL, 1.0 mol, 4.0eq) is added dropwise (over 15 min) and the resulting mixture is stirredat reflux for 1.5 h. The mixture is allowed to cool to RT and thenconcentrated in vacuo. The residue is dissolved in DCM (100 mL) to formsolution A, which is used directly in the next step.

To a stirred mixture of a given amine R₂—NH₂ (102.4 g, 1.1 mol, 1.1 eq)and triethylamine (280 mL, 2.0 mol, 2.0 eq) in DCM (700 mL), solution Ais added dropwise while keeping the reaction temperature below 10° C.The resulting mixture is allowed to warm to RT and then stirred at RTovernight. The reaction mixture is diluted with ice-water (1.0 L) andstirred for 15 min. The precipitate is collected by filtration, rinsedwith isopropyl ether (3×100 mL) and petroleum ether (3×100 mL), and thendried in vacuo to afford product amide (F-2).

A mixture of nitro-benzamide (F-2) (20.0 mmol, 1.0 eq) and DMF (cat.) intoluene (60 mL) at RT, thionyl chloride (12 mL, 164 mmol, 8.2 eq) isadded dropwise (over 5 min) and the resulting mixture is stirred atreflux for 2 h. The mixture is allowed to cool to RT and thenconcentrated in vacuo. The residue is dissolved in DCM (10 mL) to formsolution B, which is used directly in the next step.

To a stirred mixture of N-(tert-butoxycarbonyl)-L-alanine (16.0 mmol,0.8 eq) and N,N-diisopropylethylamine (4.0 g, 31.0 mol, 1.5 eq) in DCM(20 mL), solution B is added dropwise while keeping the reactiontemperature between 0-10° C. The resulting mixture is stirred at thistemperature for 1 h and then stirred at RT overnight. The reactionmixture is quenched with ice-water (100 mL). The organic layer isseparated and the aqueous layer is extracted with DCM (2×80 mL). Thecombined organic layers are washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo and the residue isslurried in isopropyl ether (100 mL) for 15 min. The solid is collectedby filtration and dried in vacuo to afford product (F-3).

To a suspension of zinc dust (7.2 g, 110 mmol, 10.0 eq) in glacialacetic acid (40 mL) at 15° C., a solution of (F-3) (11.0 mmol, 1.0 eq)in glacial acetic acid (40 mL) is added and the resulting mixture isstirred at RT for 4 h. The mixture is poured into ice-water (200 mL) andneutralized with saturated aqueous NaHCO₃ solution to adjust the pH to8. The resulting mixture is extracted with DCM (3×150 mL). The combinedorganic layers are washed with brine, dried over Na₂SO₄ and filtered.The filtrate is concentrated in vacuo and the residue is purified byflash chromatography on silica gel (7% ethyl acetate-petroleum ether) toafford product (F-4).

Compound (F-4) (0.5 mmol, 1.0 eq) is dissolved in hydrochloric methanolsolution (2N, 20 mL) and the resulting mixture is stirred at RT for 2 h.The mixture is concentrated in vacuo. The residue is diluted with water(30 mL) and then neutralized with saturated aqueous NaHCO₃ to adjust thepH to 8 while keeping the temperature below 5° C. The resulting mixtureis extracted with DCM (3×30 mL). The combined organic layers are washedwith brine, dried over Na₂SO₄ and filtered. The filtrate is concentratedin vacuo and the residue is slurried in petroleum ether (10 mL). Thesolid is collected by filtration and dried in vacuo to afford product(F-5).

The quinazolinone (F-5) can be used to synthesize compounds describedherein using, for example, Method D to couple the amine to W_(d) groups.

General conditions for the preparation of(S)-3-(1-aminoethyl)1-8-(trifluoromethyl)isoquinolin-1(2H)-ones

To a suspension of 2-amino-6-methylbenzoic acid (G-1) (20.0 g, 132.0mmol, 1.0 eq) in H₂O (55 mL) at 0-5° C., conc. HCl (36.5%, 64 mL, 749mmol, 5.7 eq) is added slowly. After stirring for 15 min, the mixture isadded dropwise to a solution of sodium nitrite (12.02 g, 174.0 mmol,1.32 eq) in H₂O (36 mL) at 0-5° C., and the resulting mixture is stirredfor 1 h. The resulting solution is then added to a solution of KI (60.5g, 364.5 mmol, 2.76 eq) in H₂O (150 mL) at 0-5° C. The reaction mixtureis allowed to warm to RT and stirred at RT overnight. The mixture isextracted with ethyl acetate (3×100 mL). The combined organic layers arewashed with water (2×100 mL), dried over anhydrous Na₂SO₄ and filtered.The filtrate is concentrated in vacuo and the residue is purified byflash column chromatography on silica gel (0-20% ethyl acetate-petroether) to afford the product, 2-iodo-6-methylbenzoic acid (G-2).

To a stirred mixture of 2-iodo-6-methylbenzoic acid (G-2) (305.3 mmol,1.0 eq) and DMF (0.3 mL) in DCM (350 mL) at RT, oxalyl chloride (466.4mmol, 1.5 eq) is added dropwise. The resulting mixture is stirred at RTfor 3 h and then concentrated in vacuo. The residue is dissolved in DCM(50 mL) and the resulting solution (solution A) is used directly in thenext step.

To a stirred mixture of R₃-substituted aniline (335.7 mmol, 1.1 eq) andtriethylamine (915.0 mmol, 3.0 eq) in DCM (350 mL), solution A (150 mL)is added dropwise while the reaction temperature is controlled below 30°C. by an ice-water bath. The reaction mixture is stirred at RT for 1 hand then quenched with water (200 mL). The organic layer is separated,washed with water (2×200 mL), dried over anhydrous Na₂SO₄ and filtered.The filtrate is concentrated in vacuo. The product is rinsed withisopropyl ether and dried in vacuo to afford the product amide (G-3).

A mixture of amide (G-3) (18.0 mmol, 1.0 eq), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (72.9 mmol, 4.0 eq) and CuI (3.63mmol, 0.2 eq) in DMF (130 mL) is stirred at 70° C. under an argonatmosphere overnight. The mixture is allowed to cool to RT and thenconcentrated in vacuo to remove the solvent. The resulting residue ispartitioned between ethyl acetate (60 mL) and water (60 mL), and theaqueous layer is extracted with ethyl acetate (2×60 mL). The combinedorganic layers are washed with water (2×60 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate is concentrated in vacuo and theresidue is purified by flash column chromatography on silica gel toafford the product, trifluoromethyl amide (G-4).

To a stirred mixture of amide (G-4) (10.1 mmol, 1.0 eq) in anhydrous THF(25 mL) at 40° C. under an argon atmosphere, a solution ofn-butyllithium in THF (2.5 M, 25.3 mmol, 2.5 eq) is added dropwise (over15 min) and the inner temperature is controlled between −30° C. and −20°C. during the addition. The resulting mixture is stirred at −30° C. foran additional 1 h. To a stirred mixture of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (11.1 mmol, 1.1 eq)in anhydrous THF (20 mL) at −30° C. under an argon atmosphere, asolution of isopropylmagnesium chloride in THF (12.6 mmol, 1.25 eq) isadded dropwise (over 15 min) and the inner temperature is controlledbelow −20° C. during the addition. The resulting mixture is stirred at−15° C. for 1 h. This solution is then slowly added to above reactionmixture at −30° C. (over 10 min), and the resulting mixture is stirredat −30° C. for an additional 30 min. The reaction mixture is quenchedwith water (50 mL) and then acidified with conc. HCl at −5° C. to adjustthe pH to 5. The mixture is allowed to warm to RT and concentrated invacuo. The residue is dissolved in MeOH (10 mL), and then conc. HCl (10mL) is added quickly at RT. The resulting mixture is stirred at refluxfor 2 h, cooled to RT and then concentrated in vacuo. The residue issuspended in water (15 mL), basified with concentrated ammoniumhydroxide to adjust the pH to 9-10 while keeping the inner temperaturebelow 5° C. and then extracted with DCM (3×15 mL). The combined organiclayers are washed with brine, dried over MgSO₄ and filtered. Thefiltrate is concentrated in vacuo and the residue is dissolved in MeOH(70 mL). To this solution, D-(−)-tartaric acid (8.1 mmol, 0.8 eq) isadded in one portion at RT. After stirring at RT for 30 min, a solidprecipitates and the mixture is slurried at RT for 10 h. The precipitateis collected by filtration and rinsed with MeOH (3×4.0 mL). Thecollected solid is suspended in water (30 mL) and then neutralized withconcentrated ammonium hydroxide solution at RT to adjust the pH to 9-10.The mixture is extracted with DCM (3×15 mL). The combined organic layersare washed with brine, dried over anhydrous MgSO₄ and filtered. Thefiltrate is concentrated in vacuo to afford the product,(S)-3-(1-aminoethyl)-8-(trifluoro methyl)isoquinolin-1(2H)-one (G-5).

General conditions for the preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones

An o-methylbenzoic acid (H-1) (46.9 mmol, 1 eq) in a flame-dried roundbottom flask under nitrogen is dissolved in THF (50 mL). The resultinghomogeneous yellow solution is cooled to 25° C. and n-hexyllithium (202mmol, 4.3 eq) (2.3 M in hexanes) is slowly added, after which thesolution becomes dark red and is stirred at 20° C. for 20 min.

(S)-Tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (61.0mmol, 1.3 eq) is charged into a second dry round bottom flask under N₂and suspended in 70 mL of dry THF and cooled to −10° C. Isopropylmagnesium chloride (2 M, 127 mmol, 2.7 eq) is slowly added resulting ina clear yellow solution. This solution is then slowly cannulateddropwise into the first round bottom flask. After addition is complete,the dark solution is slowly warmed to RT and stirred at RT for 2 h. Thereaction mixture is then recooled to −10° C. and quickly cannulated intoanother flask fitted with 15 mL of ethyl acetate and 10 mL of isobutyricacid at −10° C. under N₂. During this time the mixture goes from orangeand cloudy to clear and homogeneous. After addition, the mixture isstirred for 5 min after which water (10 mL) is rapidly added and it isstirred vigorously for 10 min at RT.

The mixture is then transferred to a separation funnel, and water (200mL) is added to dissolve salts (pH˜9). The water layer is extracted withEtOAc (3×400 mL). The aqueous layer is then acidified with HCl (2 M) topH 3, and then extracted with EtOAc (3×500 mL), dried over sodiumsulfate and concentrated to provide crude material which is filteredunder vacuum through a pad of silica gel using a MeOH/DCM (gradient of2-10% MeOH) to provide the acid H-2 after concentration.

A 50 mL round bottom flask with a stir bar is filled with benzoic acidH-2 (14.63 mmol) in acetic anhydride (10 mL) and then stirred at 70° C.for 2.5 hours until complete conversion to the product is indicated byLC/MS. The acetic anhydride is evaporated under reduced pressure and thecrude residue is purified with combiflash (gradient of EtOAc/hexanes) togive the lactone H-3.

A 50 mL dry round bottom flask with a stir bar is filled with amineR₂NH₂ (1.54 mmol, 5.1 eq) in 2 mL of DCM after which trimethylaluminum(1.54 mmol, 5.1 eq) is added to the solution and stirred for 15 min. Asolution of lactone H-3 (0.31 mmol, 1.0 eq) in 2 mL of DCM is thenadded. The mixture is then stirred at RT for 3 h until LC/MS analysisshowed complete formation of the desired product. The reaction mixtureis quenched with 10 mL of Rochelle's salt and stirred for 2 h. Themixture is then diluted with DCM, washed with brine, dried with oversodium sulfate and evaporated to give a yellow sticky liquid H-4 whichis used directly in next step.

To the amide H-4 (0.31 mmol) in 5 mL of isopropanol was added 3 mL ofconcentrated HCl. The mixture is then heated in an oil bath at 65° C.for 3 h until LC/MS shows no remaining starting material. The flask isthen removed from heat and the solvents are evaporated under reducedpressure to provide a yellow solid. The resultant solid is thensuspended in 15 mL DCM after which 10 mL of saturated sodium bicarbonateis added and stirred at RT for 30 min. An additional 50 mL of DCM isthen added and organic layer separated from the aqueous layer and driedover Na₂SO₄ and concentrated to provide crude amine product H-5 which isused directly in subsequent transformations.

Example 1

Amine 1 was prepared according the Method A and then coupled to2-aminothiazole-5-carboxylic acid using Method D to provide compound 2.ESI-MS m/z: 425.0 [M+H]⁺.

The following compounds were also prepared according to the analogousprocedure of Method D from amine 1:

Example Compound Acid Found ESI-MS m/z: 2

419.0 [M + H]⁺ 3

420.0 [M + H]⁺ 4

419.0 [M + H]⁺ 5

419.0 [M + H]⁺ 6

420.0 [M + H]⁺ 7

393.0 [M + H]⁺ 8

408.0 [M + H]⁺ 9

419.0 [M + H]⁺ 10

448.0 [M + H]⁺ 11

439.0 [M + H]⁺ 12

444.0 [M + H]⁺ 13

405.0 [M + H]⁺ 14

498.0 [M + H]⁺

Example 15

Amine 16 was prepared according to Method B and then coupled to3-aminopyrazine-2-carboxylic acid using Method D to provide compound 17.ESI-MS m/z: 406.0 [M+H]⁺.

Example 16

Amine 18 was prepared according to Method A and then coupled to3-aminopyrazine-2-carboxylic acid using Method D to provide compound 19.ESI-MS m/z: 438.2 [M+H]⁺.

Example 17

Amine 18 was coupled to imidazo[1,2-b]pyridazine-3-carboxylic acid usingMethod D to provide compound 20. ESI-MS m/z: 462.0 [M+H]⁺.

Example 18

Amine 1 was coupled to imidazo[1,2-a]pyridine-3-carboxylic acid usingMethod E to provide compound 21. ESI-MS m/z: 443.06 [M+H]⁺.

The following compounds were also prepared from amine 1 according to theanalogous procedure of Method E:

Example Compound Acid Found ESI-MS m/z: 19

444.06 [M + H]⁺ 20

454.08 [M + H]⁺ 21

393.01 [M + H]⁺ 22

455.08 [M + H]⁺ 23

454.02 [M + H]⁺ 24

442.99 [M + H]⁺ 25

420.96 [M + H]⁺ 26

435.00 [M + H]⁺ 27

443.99 [M + H]⁺ 28

453.02 [M + H]⁺ 29

442.99 [M + H]⁺ 30

442.06 [M + H]⁺ 31

410.00 [M + H]⁺ 32

462.05 [M + H]⁺ 33

426.00 [M + H]⁺ 34

420.02 [M + H]⁺ 35

420.00 [M + H]⁺ 36

409.00 [M + H]⁺ 37

442.93 [M + H]⁺ 38

453.95 [M + H]⁺ 39

496.05 [M + H]⁺ 40

454.93 [M + H]⁺ 41

420.93 [M + H]⁺ 42

454.95 [M + H]⁺ 43

457.93 [M + H]⁺ 44

474.00 [M + H]⁺ 45

443.92 [M + H]⁺ 46

458.00 [M + H]⁺

Example 47

To a solution of(S)-2-amino-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)thiazole-5-carboxamide(2) (100 mg, 0.24 mmol) and triethylamine (0.07 mL, 0.48 mmol) inanhydrous THF (5 mL), acetyl chloride (0.025 mL, 0.35 mmol) and4-(dimethylamino)pyridine (2.5 mg, 0.02 mmol) were added and theresulting mixture was stirred at RT for 4 h. The mixture was partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over Na₂SO₄ and filtered. The filtrate was concentrated invacuo and the residue was purified by ISCO column chromatography (silicagel cartridge, 0-10% MeOH-DCM) to afford the product,(S)-2-acetamido-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)thiazole-5-carboxamide(compound 50). ESI-MS m/z: 467.0 [M+H]⁺.

Example 48

To a mixture of(S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (1) (50 mg,0.17 mmol) in a mixture of N,N-dimethylacetamide (1 mL) and THF (3 mL),triethylamine (0.07 mL, 0.50 mmol) and nicotinoyl chloride hydrochloride(32 mg, 0.18 mmol) were added and the resulting mixture was stirred atRT for 30 min. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and purifiedby ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) toafford the product,(S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)nicotinamide(compound 51). ESI-MS m/z: 404.0 [M+H]⁺.

Example 49

Compound 52 was prepared from the coupling of 2-bromonicotinic acid tocompound 1 using Method A. Compound 52 was then converted to compound 53according to the following procedure:

To a mixture of(S)-2-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)nicotinamide(52) (150 mg, 0.31 mmol) in anhydrous 1,4-dioxane (3 mL) in a sealedtube, morpholine (1 mL, excess amount) was added and the resultingmixture was stirred at 140° C. for 6 h. The mixture was allowed to coolto RT and then partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo and the residue was purified by ISCOcolumn chromatography (silica gel cartridge, 0-10% MeOH-DCM) followed byprep-TLC plate purification (10% MeOH-DCM) to afford the product(S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-2-morpholinonicotinamide(compound 53). ESI-MS m/z: 489.0 [M+H]⁺.

Example 50

To a solution of(S)-3-amino-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazine-2-carboxamide(4) (100 mg, 0.24 mmol) in anhydrous N,N-dimethylacetamide (6 mL),1-methyl-1H-pyrazol-4-ylboronic acid (78 mg, 0.4762 mmol), PdCl₂(dppf)(16 mg, 0.019 mmol) and aqueous Na₂CO₃ solution (1.0 M, 0.72 mL, 0.72mmol) were added sequentially. The resulting mixture was purged withargon and then stirred at 120° C. under argon for 17 h. The mixture wasallowed to cool to RT and ice-water was added. The precipitate wascollected by filtration, rinsed with water and dried in vacuo. The solidcollected was further purified by ISCO column chromatography (silica gelcartridge, 0-8% MeOH/DCM) to afford the product(S)-3-amino-N-(1-(8-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazine-2-carboxamide(compound 54). ESI-MS m/z: 466.2 [M+H]⁺.

Example 51

Compound 55 was prepared in analogous fashion to compound 54 in Example50 except that 3-pyridyl boronic acid was used in place of1-methyl-1H-pyrazol-4-yl)boronic acid. ESI-MS m/z: 463.0 [M+H]⁺.

Example 52

To a solution of(S)-3-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazine-2-carboxamide(12) (133 mg, 0.30 mmol) in anhydrous 1,4-dioxane (6 mL) in a sealedtube, methylamine hydrochloride (102 mg, 1.51 mmol) andN,N-diisopropylethylamine (0.25 mL, 1.51 mmol) were added sequentially.The resulting mixture was stirred at 140° C. in a sealed tube for 14 h.The mixture was allowed to cool to RT and then partitioned between ethylacetate and water. The organic layer was washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by ISCO column chromatography (silica gelcartridge, 0-8% MeOH-DCM) to afford the product(S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-3-(methylamino)pyrazine-2-carboxamide(compound 56). ESI-MS m/z: 434.0 [M+H]⁺.

Example 53

Compound 57 was prepared in analogous fashion to compound 56 in Example52 except that cyclopropyl amine was used in place of methyl amine.ESI-MS m/z: 460.0 [M+H]⁺.

Example 54

Compound 58 was prepared from compound 52 according to the followingprocedure:

To a solution of(S)-2-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)nicotinamide (52) (125 mg, 0.26 mmol) in a 1:1 mixture of DMF and EtOH(9 mL), 1H-pyrazole-4-boronic acid (37 mg, 0.34 mmol),tetrakis(triphenylphosphine)palladium (0) (21 mg, 0.018 mmol) andaqueous Na₂CO₃ solution (1.0 M, 0.78 mL, 0.78 mmol) were addedsequentially. The resulting mixture was stirred at 85° C. for 16 h. Themixture was allowed to cool to RT and then partitioned between ethylacetate and water. The organic layer was washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by prep-TLC plate (10% MeOH-DCM) to afford theproduct(S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-2-(1H-pyrazol-4-yl)nicotinamide(compound 58). ESI-MS m/z: 471.0 [M+H]⁺.

Example 55

Compound 59 was prepared in analogous fashion to compound 54 in Example50 except that 1H-pyrazol-3-ylboronic acid was used in place of1-methyl-1H-pyrazol-4-ylboronic acid. ESI-MS m/z: 452.2 [M+H]⁺.

Example 56

Amine 60 was prepared according the Method C and then coupled to3-aminopyrazine-2-carboxylic acid using Method D to provide compound 61.ESI-MS m/z: 407.2 [M+H]⁺.

Example 57

Amine 18 was coupled to pyrazolo[1,5-a]pyrimidine-3-carboxylic acidusing Method D to provide compound 62. ESI-MS m/z: 462.2 [M+H]⁺.

Example 58

To a suspension of amine 1 (1.34 mmol, 1.0 equiv) in DMF (12 mL) wasadded DIEA (3.68 mmol, 2.0 equiv), and then Boc-anhydride (1.47 mmol,1.1 equiv). The reaction mixture was stirred at RT overnight after whichit was quenched with 6 M NaOH (100 μL) and stirred for 15 min, thendiluted with water (60 mL) and HOAc (1 mL) and stirred in an ice bathfor 30 min. The resulting precipitate was collected by filtration,washed with water (˜4×10 mL) and dried in vacuo to provide the carbamate63. ESI-MS m/z: 399.05 [M+H]⁺.

Example 59

A microwave tube with stir bar was filled with carbamate 63 (0.63 mol,1.0 eq), potassium pyrazole-3-borontrifluoride (0.69 mmol, 1.1 eq),sodium carbonate (1.88 mmol, 3.0 eq), Pd(OAc)₂ (0.038 mmol, 6 mol %),and RuPhos (0.075 mmol, 12 mol %), capped, and purged with argon.Ethanol (3.4 mL) was added and the reaction was subjected to microwaveheating at 100° C. for 22 h. The reaction mixture was then directlypurified using flash silica gel chromatography (gradient 30-70% ethylacetate/hexanes) to provide compound 64. ESI-MS m/z: 431.11 [M+H]⁺.

Example 60

Amine 18 was coupled to 1,6-naphthyridine-8-carboxylic acid using MethodD to provide compound 65. ESI-MS m/z: 473.10 [M+H]⁺.

Example 61

Amine 66 was prepared using Method G. It was then coupled to1,6-naphthyridine-8-carboxylic acid using Method D to provide compound67. ESI-MS m/z: 489.4 [M+H]⁺.

Example 62

Amine 1 was coupled to thieno[3,2-b]pyridine-3-carboxylic acid usingMethod D to provide compound 68. ESI-MS m/z: 460.2 [M+H]⁺.

Example 63

2-(tert-Butoxycarbonylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidwas synthesized according to WO2011/03065 A2. The acid was then coupledto compound 1 according to the following procedure:

Compound 1 (1.0 eq),2-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(1.1 eq), HOBt (1.0 eq) and EDC (1.1 eq) were weighed into a vial andthe mixture was dissolved in 6 mL DMF (0.08 M). Hunig's base (2.0 eq)was added and the reaction was placed on an orbital stirrer at RTovernight. After 14 h, the reaction was diluted with 10 mL saturatedNaHCO₃ and a white solid crashed out. The mixture was diluted with anadditional 10 mL of water and the solid was collected by filtration toprovide amide 69 as an off-white solid. The amide was then dissolved in4 mL methylene chloride, to which TFA (4 mL) is added. The reaction wasstirred at room temperature for 30 min, then the solvent was removedunder a stream of N₂. Saturated NaHCO₃ (10 mL) and water (10 mL) wereadded to the crude residue and the resulting solid was collected byfiltration to provide compound 70 as a white solid. ESI-MS m/z: 459.2[M+H]⁺.

The following examples were prepared in analogous fashion as compound 70from the corresponding amine starting material synthesized by generalmethods indicated in the table below:

Amine Starting Material Example Compound Preparation Method Found ESI-MSm/z: 64

  71 G 493.4 [M + H]⁺ 65

  72 A 477.4 [M + H]⁺ 66

  73 H 425.4 [M + H]⁺ 67

  74 H 397.1 [M + H]⁺ 68

  75 H 495.1 [M + H]⁺ 69

  76 F 460.1 [M + H]⁺ 70

  77 A 423.2 [M + H]⁺ 71

  78 A 477.1 [M + H]⁺

Example 72

Amine 1 was coupled to 3-amino-5-methylpyrazine-2-carboxylic acid usingMethod D to provide compound 79. ESI-MS m/z: 434.4 [M+H]⁺.

Example 73

Amine 66 was coupled to 3-amino-5-methylpyrazine-2-carboxylic acid usingMethod D to provide compound 80. ESI-MS m/z: 468.1 [M+H]⁺.

Example 74

Amine 1 was coupled to 3-aminoquinoxaline-2-carboxylic acid using MethodD to provide compound 81. ESI-MS m/z: 470.3 [M+H]⁺.

Example 75

Amine 1 was coupled to 5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid using Method D to provide compound 82. ESI-MS m/z: 458.1 [M+H]⁺.

Example 76

Compound 15 (0.25 mmol, 1.0 eq), 3-(N-methylsulfamoyl)phenylboronic acid(1.5 eq), sodium carbonate (2.0 eq) and palladiumtetrakis(triphenylphosphine) (15 mol %) was suspended in dioxane/water(2 mL, 4:1 v/v) and purged with argon for 2 min. The reaction vessel wassealed and heated to 90° C. for 24 h. The reaction mixture was thentransferred to separatory funnel and combined with excess water andethyl acetate. The water layer was extracted with ethyl acetate (1×) andthe organic layers were combined and washed with brine (1×), dried withsodium sulfate and pre-absorbed onto silica gel. The material was thenpurified by flash column chromatography (ISCO Combiflash,aceteone/methylene chloride) to provide compound 83. ESI-MS m/z: 589.2[M+H]⁺.

The following compounds were prepared using analogous procedures toExample 76, from the appropriate boronic acid and compound 15:

Example Compound Boronic Acid ESI-MS m/z  77

  84

574.5 [M + H]⁺  78

  85

589.2 [M + H]⁺  79

  86

631.2 [M + H]⁺  80

  87

572.2 [M + H]⁺  81

  88

588.2 [M + H]⁺  82

  89 MeB(OH)₂ 434.1 [M + H]⁺  83

  90

574.2 [M + H]⁺  84

  91

603.3 [M + H]⁺  85

  92

629.3 [M + H]⁺  86

  93

556.3 [M + H]⁺  87

  94

544.5 [M + H]⁺  88

  95

643.5 [M − 1]  89

  96

615.5 [M + H]⁺  90

  97

617.5 [M + H]⁺  91

  98

555.5 [M + H]⁺  92

  99

618.5 [M + H]⁺  93

  100

658.6 [M + H]⁺  94

  101

619.2 [M + H]⁺  95

  102

615.2 [M + H]⁺  96

  103

589.5 [M + H]⁺  97

  104

512.5 [M + H]⁺  98

  105

526.5 [M + H]⁺  99

  106

554.2 [M + H]⁺ 100

  107

590.2 [M + H]⁺ 101

  108

575.2 [M + H]⁺ 102

  109

500.2 [M + H]⁺ 103

  110

486.2 [M + H]⁺

Example 104

Compound 15 (0.245 mmol, 1.0 eq) was dissolved in N,N-dimethyl formamide(40 mL), to which copper (I) cyanide (2.0 eq) and copper (I) iodide (0.7eq) were added. The mixture was degassed with argon for 10 min, thenpalladium tetrakis(triphenylphosphine) was added. The mixture was heatedto 80° C. for 2 h. The reaction mixture was cooled, and then partitionedbetween water and methylene chloride. The mixture was filtered. Theorganic layer was washed with brine, dried over sodium sulfate andpre-absorbed onto silica gel. The material was purified by flash columnchromatography (ISCO Combiflash, aceteone/methylene chloride) to providecompound 111. ESI-MS m/z: 445.1 [M+H]⁺.

Example 105

Compound 15 (0.23 mmol, 1.0 eq) was suspended in N,N-dimethylformamide,and 4-(tributylstannyl)thiazole (1.0 eq) was added. The mixture waspurged with argon for 10 min, then palladiumtetrakis(triphenylphosphine) (15 mol %) was added. The mixture waspurged with argon for an additional 5 min, and the reaction vessel wasthen sealed and heated to 90° C. for 1 h. The reaction mixture wascooled and diluted with water and ethyl acetate. The organic phase waspre-adsorbed on silica gel. The resulting material was purified by flashcolumn chromatography (ISCO Combiflash, aceteone/methylene chloride) toprovide compound 112. ESI-MS m/z: 503.1 [M+H]⁺.

Example 106

Compound 113 was prepared in analogous fashion to compound 112 inExample 105 except that 2-(methylsulfonyl)-4-(tributylstannyl)thiazolewas used in place of 4-(tributylstannyl)thiazole. ESI-MS m/z: 581.1[M+H]⁺.

Example 107

Compound 115 was prepared from compound 1 according the followingprocedures:

Compound 1 (2.0 mmol, 1.0 eq), phenylboronic acid (3.0 mmol, 2.0 eq),sodium carbonate (10.0 mmol, 5.0 eq) and Pd(dppf)₂Cl₂.CH₂Cl₂ (20 mol %)in 12 mL degassed dioxane-water (4:1 v/v) was purged with argon for 15min and then heated to 90-100° C. for 2 h. The mixture was cooled,diluted with 10 mL EtOAc and 10 mL water. The aqueous layer wasextracted with 3×10 mL ethyl acetate. The combined organic layers werefiltered though a pad of Celite and the filtrate was were washed with3×10 mL water, dried over sodium sulfate, and the solvents were removedunder reduced pressure to give compound 114 as a brownish solid. ESI-MSm/z: 341.4 [M+H]⁺.

Conversely, the conversion from compound 1 to compound 114 can becarried out with these conditions: Compound 1 (2.0 mmol, 1.0 eq),phenylboronic acid (1.1 eq), and potassium phosphate monohydrate (2.0eq) were charged to a reaction vessel. 1-BuOH (2.4 mL) and water (1.2mL) were charged to the reaction vessel after which it was purged withN₂ for 30 min. The Pd(amphos)Cl₂ (1 mol %) was added while the mixturewas continuously sparged with N₂ for a minimum of 10 min after which themixture was heated to 80° C. for 4 h until there was no more startingmaterial as indicated by LC/MS analysis. The reaction was allowed tocool and the layers were separated. The aqueous layer was stirred with1-BuOH (1.2 mL) for 10 min. The organic layers were combined andconcentrated to provide material which was used directly in the nextstep.

Compound 114 was then converted to compound 115 using analogousprocedure to Example 63. ESI-MS m/z: 501.2 [M+H]⁺.

The following compounds were prepared using analogous procedures toExample 107, from the appropriate boronic acid and compound 1, using oneof the Suzuki coupling conditions outlined above, followed by amideformation analogous to Example 63:

Example Compound Boronic Acid ESI-MS m/z 108

  116

532.2 [M + H]⁺ 109

  117

502.2 [M + H]⁺ 110

  118

502.2 [M + H]⁺ 111

  119

532.2 [M + H]⁺ 112

  120

595.2 [M + H]⁺ 113

  121

532.2 [M + H]⁺

Example 114

Amine 122 was prepared according to Method A. Amine 122 was thenconverted to compound 123 in analogous fashion to compound 70 in Example63. ESI-MS m/z: 439.6 [M+H]⁺.

Example 115

Ethyl 3,5-diamino-1H-pyrazole-4-carboxylate (9.2 mmol, 1.0 eq) wasdissolved in N,N-dimethyl formamide (20 mL) and cesium carbonate (1.5eq), and ethyl 3-ethoxyacrylate (1.5 eq) were added. The reaction washeated to 110° C. for 16 h. The mixture was cooled. Acetic acid (1.2 mL)was added, followed by 90 mL of water. The mixture was stirred until asolid formed, which was collected by filtration, and washed with excesswater to provide compound 124.

Compound 124 (1.15 mmol, 1.0 eq) was dissolved in 5 mL methylenechloride. Hunig's base (2.6 eq) was added, followed by triflic anhydride(1.1 eq). The reaction mixture was stirred at room temperature for 30min. The mixture was concentrated under argon, and then resuspended indioxane/water (6 mL, 4:1 v/v). 3-Methyl-sulfonylboronic acid (1.36 eq),AmPhos (10 mol %) and sodium carbonate (2 eq) were added. The reactionmixture was then sealed and heated to 80° C. for 30 min. The mixture wastransferred to a separatory funnel with excess water. The mixture wasextracted with methylene chloride (3×). The organic layers werecombined, dried over sodium sulfate, and purified by flash silica gelcolumn chromatography to provide compound 125.

Compound 125 (0.50 mmol) was dissolved in 10 mL ethanol, and LiOH (16eq) was added. The mixture was heated to 70° C. for 1.5 h, and stirredfor 16 h at room temperature. The reaction was then quenched with 5%citric acid (5 mL). Ethanol was removed under reduced pressure, and theresulting material was isolated by filtration and washed with excessethyl acetate, 5% citric acid solution, water and ethyl acetate toprovide acid 126.

Acid 126 was then coupled to amine 1 using Method D to provide compound127. ESI-MS m/z: 613.4 [M+H]⁺.

Example 116

Compound 128 was prepared in analogous fashion to compound 115 inExample 107 except that (2-methoxypyrimidin-5-yl)boronic acid was usedin place of phenyl boronic acid. ESI-MS m/z: 533.2 [M+H]⁺.

Example 117

A round bottom flask was charged with compound 69 (0.88 mmol, 1.0 eq),bis(pinacolato)diborone (3.0 eq), Pd₂(dba)₃ (5 mol %), Xphos (10 mol %)and potassium acetate (3.0 eq). The vial was evacuated and filled withAr. Degassed dioxane was added and the reaction was stirred at 110° C.for 8 h. The mixture was then diluted with ethyl acetate (50 mL) andwashed with water (15 mL) and brine and dried. The crude was purifiedwith Combiflash column to give a mixture of Compound 129 and Compound130.

Compound 129 (0.65 mmol) was dissolved in 10 mL THF after which 1 M NaOH(2 mL) was added followed by 30% H₂O₂ in water (0.67 mL). The mixturewas stirred at room temperature after which it was diluted with ethylacetate, transferred to a separatory funnel, washed with water, brine,dried and concentrated. The crude residue was purified by Combiflashcolumn to provide Compound 131.

Compound 131 was deprotected in analogous fashion as Compound 69 inExample 63 to provide the amine compound 132. ESI-MS m/z: 441.4 [M+H]⁺.

Example 118

Compound 130 was deprotected in analogous fashion as Compound 69 inExample 63 to provide the amine compound 133. ESI-MS m/z: 425.4 [M+H]⁺.

Example 119

To a solution of 2-iodo-3-methylpyridine (42.3 mmol, 1.0 eq) in DCE (90mL), N-bromosuccinimide (1.1 eq) was added. The resulting mixture washeated to 85° C. stirred for 6 h. The mixture was cooled to RT,pre-adsorbed on silica gel and purified on silica gel column with ethylacetate and hexanes to afford bromide 134.

Compound 134 (4.4 mmol, 1.0 eq) was dissolved in ethanol (20 mL) afterwhich 28% ammonium hydroxide (5.5 eq) was added. The resulting mixturewas stirred at RT for 16 h. The solvent was removed, the residue waspre-adsorbed on silica gel and purified on silica gel column withmethanol and dichloromethane to afford amine 135.

To a solution of 2-cyanoacetyl chloride (5.1 mmol, 1.0 eq) in DCM (10mL) at 0° C., Compound 1 (1.0 eq) and triethylamine (1.5 eq) were added.The resulting mixture was warmed to RT and stirred for 2 h. The mixturewas partitioned between DCM and a saturated aqueous sodium bicarbonatesolution. The organic phase was separated, dried with sodium sulfate,pre-adsorbed on silica gel and purified on silica gel column withacetone and DCM to afford nitrile 136. ESI-MS m/z: 366.3 [M+H]⁺.

To a solution of compound 135 (0.46 mmol, 1.0 equiv) in DMSO (2 mL),diisopropylethylamine (2.0 eq), nitrile 136 (2.0 eq) and copper (I)bromide (2.0 eq) were added, and the resulting mixture was stirred at RTfor 1.5 h. The reaction mixture was poured into a mixture of2-methyltetrahydrofuran (15 mL) and a 10% aqueous ammonia solution (15mL). The resulting mixture was vigorously stirred at RT for 16 h.Stirring was stopped, the phases were separated and the aqueous layerwas extracted with 2-methyltetrahydrofuran. The combined organic layerswere dried with sodium sulfate, pre-adsorbed on silica gel and purifiedon silica gel column with acetone and DCM to afford naphthyridine 137.ESI-MS m/z: 470.1 [M+H]⁺.

Example 120

Compound 138 was prepared in analogous fashion to Compound 115 inExample 107 except that2-isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine wasused in place of phenyl boronic acid. ESI-MS m/z: 560.3 [M+H]⁺.

Example 121

Compound 139 was prepared in analogous fashion to Compound 116 inExample 108 except that the amine was coupled to3-amino-5-methylpyrazine-2-carboxylic acid. ESI-MS m/z: 507.1 [M+H]⁺.

Example 122

A mixture of chloride 137 (28 mg, 0.060 mmol), 2-methoxypyridin-4-ylboronic acid (2.0 eq), Pd(amphos)₂ (10 mol %) and sodium carbonate (2.5eq) in dioxane/water (4/1 v/v, 3 mL) was degassed with Ar for 10 min.The resulting mixture was heated to 85° C. and stirred for 16 hr. Theresulting suspension was cooled to RT, partitioned between DCM and asaturated aqueous sodium chloride solution. The organic phase wasseparated, dried with sodium sulfate, pre-adsorbed on silica gel andpurified on silica gel column with acetone and DCM to afford thenaphthylidine compound 140. ESI-MS m/z: 543.2 [M+H]⁺.

Example 123

Compound 142 was prepared in 3 steps from ethyl3,5-diamino-1H-pyrazole-4-carboxylate in the following manner: Ethyl3,5-diamino-1H-pyrazole-4-carboxylate (1.0 eq, 2.8 mmol) was dissolvedin 6 mL N,N-dimethylformamide. 4,4-Dimethyoxy-2-butanone (2.0 eq) wasadded and the reaction was heated to 110° C. for 1 h, after which aceticacid (1.0 eq) was added and the reaction was heated for an additional 2h. The mixture was allowed to cool and was neutralized with saturatedsodium bicarbonate, transferred to a separatory funnel and extractedwith 1× ethyl acetate and 2× methylene chloride. The organic layers werecombined, dried over MgSO₄ and concentrated until there was <20 mL ofsolvent remaining. Excess hexanes were added until a solid crashed out.The resulting solid was collected via vacuum filtration to provide thedesired pyrazolopyrimidine. This solid (0.59 mmol, 1.0 eq) was thendissolved in ethanol/water (10 mL, 1:1 v/v). Lithium hydroxide (30 eq)was then added and the reaction was heated to 70° C. for 2 h. Thereaction was allowed to cool, after which 3 N HCl was added dropwiseuntil the mixture had a pH<2. The resulting solid was collected viavacuum filtration and washed with excess water to provide Compound 141,which was coupled to Compound 1 according to method D to provide theamide 142. ESI-MS m/z: 473.4 [M+H]⁺.

Example 124

Amine 143 was prepared according the Method F. It was then converted toCompound 144 in two steps in analogous fashion to Compound 116 inExample 108. ESI-MS m/z: 533.5 [M+H]⁺.

Example 125

Compound 145 was prepared in analogous fashion as compound 144 inExample 124 except that2-isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine wasused in place of (2-methoxypyridin-4-yl)boronic acid. ESI-MS m/z: 561.5[M+H]⁺.

Example 126

Compound 146 was prepared according to Method A. It was then convertedto compound 147 in analogous fashion to compound 70 in Example 63.ESI-MS m/z: 485.0 [M+H]⁺.

Example 127

Amine 146 was coupled to 3-aminopyrazine-2-carboxylic acid using MethodD to provide compound 148. ESI-MS m/z: 446.4 [M+H]⁺.

Example 128

Amine 149 was prepared according to Method A. It was then converted tocompound 150 in analogous fashion to compound 116 in Example 108. ESI-MSm/z: 496.5 [M+H]⁺.

Example 129

Compound 151 was prepared in 3 steps from ethyl3,5-diamino-1H-pyrazole-4-carboxylate in the following manner: Ethyl3,5-diamino-1H-pyrazole-4-carboxylate (1.0 eq, 5.7 mmol) was dissolvedin 6 mL N,N-dimethylformamide. Pentane-2,4-dione (2.0 equiv) and aceticacid (5.0 equiv) were added and the reaction was heated to 110° C. for 2h, after which there was no more starting material by TLC analysis. Themixture was allowed to cool and was neutralized with saturated sodiumbicarbonate. The resulting solid was collected via vacuum filtration toprovide the desired pyrazolopyrimidine. This solid (4.7 mmol, 1.0 eq)was then dissolved in ethanol/water (10 mL, 1:1 v/v). Lithium hydroxide(30 equiv) was then added and the reaction was heated to 70° C. for 2 h.The reaction was allowed to cool, after which 3 N HCl was added dropwiseuntil the mixture had a pH<2. The resulting solid was collected viavacuum filtration and washed with excess water to provide Compound 151,which was coupled to Compound 1 according to method D to provide theamide 152. ESI-MS m/z: 487.4 [M+H]⁺.

Example 130

Compound 70 (0.83 mmol, 1.0 equiv), dichlorobis(acetonitrile)palladium(14 mol %), X-Phos (45 mol %), and cesium carbonate (3.0 equiv) weredissolved in propionitrile (8 mL) and 2 mL DMSO. The whole mixture wasbubbled with Ar for 10 min before the addition of propargylamine (230μL). The yellow mixture was sealed and heated in an oil bath at 103° C.for 2 h. The brownish black mixture was allowed to cool to roomtemperature and diluted with 50 mL methylene chloride and washed withwater, and brine, dried over sodium sulfate, and filtered. Silica gel(10 g) was added to the combined filtrates and the mixture wasconcentrated under reduced pressure after which it was purified onsilica gel (12 g, ISCO) through solid loading (gradient of 0-20%methanol (containing 0.1% ammonia)/methylene chloride) to provide thedesired compound 153. ESI-MS m/z: 478.4 [M+H]⁺.

Example 131

Compound 154 was prepared in analogous fashion to compound 153 inExample 130 except that but-3-yn-1-amine hydrochloride was used in placeof propargyl amine. ESI-MS m/z: 492.4 [M+H]⁺.

Example 132

Compound 153 was coupled to acrylic acid according to Method D toprovide compound 155. ESI-MS m/z: 532.5 [M+H]⁺.

The following compounds were prepared in analogous fashion from amine153 or 154:

Example Compound Acid Starting Material Found ESI-MS m/z 133

  156

616.6 [M + H]⁺ 134

  157

590.5 [M + H]⁺ 135

  158

590.6 [M + H]⁺ 136

  159

588.7 [M + H]⁺ 137

  160

546.6 [M + H]⁺ 138

  161

604.5 [M + H]⁺ 139

  162

588.5 [M + H]⁺ 140

  163

576.6 [M + H]⁺ 141

  164

596.6 [M + H]⁺ 142

  165

520.5 [M + H]⁺ 143

  166

589.5 [M + H]⁺

Example 144

A suspension of dichlorobis(acetonitrile)palladium (15 mol %), X-Phos(45 mol %), cesium carbonate (3.0 equiv), and compound 70 (0.22 mmol,1.0 equiv) in 6 mL propionitrile under argon at 22° C. was treated withpropargyl trimethyl silane (3.0 equiv) in 0.5 mL propionitrile. Theresulting yellow mixture was stirred at room temperature for 20 minbefore heating to 100° C. for 2.5 h. The brownish black mixture wascooled to room temperature, diluted with KF solution (130 mg KF in 3 mLwater), 20 mL ethyl acetate and 5 mL water. The mixture was filteredthrough a pad of celite and the filter pad was washed with ethyl acetate(2×20 mL), the combined filtrates were partitioned, and the loweraqueous layer was extracted with EtOAc (2×10 mL). The combined organiclayers were washed with water (10 mL) and brine (10 mL), dried andconcentrated under reduced pressure. The crude was purified using flashsilica gel chromatography (12 g, ISCO) using a gradient ofacetone/methylene chloride (0-20% acetone) to provide the desiredcompound 167 as a light yellow powder after lyophilization. ESI-MS m/z:463.5 [M+H]⁺.

Example 145

Compound 168 was prepared from compound 1 and3,5-diamino-6-bromopyrazine-2-carboxylic acid according to Method D. Itwas then converted to compound 169 using the analogous method forcompound 83 in Example 76. ESI-MS m/z: 604.5 [M+H]⁺.

Example 146

Compound 170 was prepared from compound 149 and3,5-diamino-6-bromopyrazine-2-carboxylic acid according to Method D. Itwas then converted to compound 171 using the analogous method forcompound 83 in Example 76. ESI-MS m/z: 553.5 [M+H]⁺.

Example 147

Compound 172 was prepared in analogous fashion to compound 171 inExample 146 except thatN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamidewas used in place of (3-(methylsulfonamido)phenyl)boronic acid. ESI-MSm/z: 554.5 [M+H]⁺.

Example 148

Compound 175 was prepared in 3 steps from ethyl3,5-diamino-1H-pyrazole-4-carboxylate in the following manner: A mixtureof ethyl 3,5-diamino-1H-pyrazole-4-carboxylate (1.5 mmol, 1.0 equiv) and1,1-dimethoxy-4-methylpentan-3-one (2.0 equiv) in DMF (4 mL) under anArgon atmosphere was stirred for 5 min at room temperature beforeheating at 110° C. for 1 h. After 1 h, acetic acid (1.0 equiv) was addedand an additional 1.0 equiv was added after 2.5 h. The reaction wasstirred and heated for 72 h after which 30 mL saturated sodiumbicarbonate was added and the mixture was filtrated. The aqueous layerwas extracted with 40 mL methylene chloride. The organic layers werecombined, washed with brine (2×30 mL), dried over magnesium sulfate andconcentrated to a crude mixture of 173 and 174 which was used directlyin the next step.

173 and 174 (1.49 mmol, 1.0 equiv) were dissolved in 8 mL of methanoland the mixture was stirred for 2 min before adding LiOH (10.0 equiv)and heating at 60° C. for 2 h. The reaction mixture was cooled down toroom temperature, methanol was removed after which 4 mL of water and 7mL of 5% citric acid were slowly added to reach pH 5. The layers wereseparated and 1 mL of citric acid (5%) was added to the aqueous layer,then back-extracted with of methylene chloride (2×5 mL). The combinedorganic layers were washed with water (2×10 mL) and brine (3×20 mL). Thecombined organic layers were dried with Na₂SO₄, filtered, and thesolvents were evaporated under reduce pressure to give a crude yellowsolid containing a mixture of 175 and 176. ESI-MS m/z: 221.3 [M+H]⁺.

The resulting mixture was coupled to Compound 1 according to method D toprovide the amide 177 after purification using flash silica gelchromatography. ESI-MS m/z: 501.3 [M+H]⁺.

Example 149

Compound 178 was also isolated from the coupling reaction in Example148. ESI-MS m/z: 501.3 [M+H]⁺.

Example 150

A mixture of amine 1 (0.45 mmol, 1.0 equiv), dimethylamine (15.0 equiv)and diisopropylethylamine (4.0 equiv) in NMP (7 mL) was degassed with Arfor 5 min. The resulting mixture was sealed and heated in a microwavereactor to 150° C. for 21 h. The resulting suspension was cooled to roomtemperature and partitioned between ethyl acetate and water. The aqueouslayer was extracted with ethyl acetate (2×) and the combined organiclayers were washed with brine, dried with sodium sulfate, pre-adsorbedon silica gel and purified on silica gel column with methanol and DCM toafford the amine 179. ESI-MS m/z: 308.4 [M+H]⁺.

Amine 179 was converted in to compound 180 in 2 steps in analogousfashion to compound 70 in Example 63. ESI-MS m/z: 468.5 [M+H]⁺.

Example 151

A mixture of 3-amino-6-bromopyrazine-2-carboxylic acid (3.90 mmol, 1.1equiv), 3-(methylsulfonamido)phenylboronic acid (1.0 equiv), sodiumcarbonate (5.0 equiv) and Pd(PPh₃)₄ (10 mol %) were sequentially addedin 30 mL 4:1 (v/v) degassed dioxane-water. The reddish brown mixture wasstirred under Ar for 2 min at room temperature before heating to 88° C.for 2.5 hours. The mixture was slowly acidified by adding 30 mL of 10%citric acid until pH=4. The mixture was cooled to 25-30° C., dilutedwith 40 mL ethyl acetate, then 20 mL water and transferred to aseparatory funnel. The aqueous layer was removed, extracted with ethylacetate (3×10 mL), the combined organic layers were washed with water(2×20 mL) and brine (3×20 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure to providecompound 181 as yellow solid which was washed with methylene chlorideand used directly in the next step. ESI-MS m/z: 309.3 [M+H]⁺.

A mixture of 181 (0.91 mmol, 1 equiv) 182 (prepared according to MethodH) (1.1 equiv), HOBt (1.5 equiv) and EDC (1.5 equiv) were dissolved in 8mL DMF under Ar, followed by DIPEA (5.0 equiv) after 2 min of stirring.The reaction was stirred at room temperature for 1.5 h and diluted with30 mL saturated sodium bicarbonate. The resulting solid was collectedvia vacuum filtration, and washed with water to provide the desiredcompound 183. ESI-MS m/z: 527.4 [M+H]⁺.

Example 152

Compound 184 was prepared in analogous fashion to compound 180 inExample 150 except that morpholine was used in place of dimethyl amine.ESI-MS m/z: 510.5 [M+H]⁺.

Example 153

A mixture of 183 (0.049 mmol, 1.0 equiv) and acetic anhydride (3.0equiv) was added in 1 mL pyridine under Ar. The reaction mixture wasstirred for 5 min at room temperature before heating to 70° C. for 3 h.The mixture was diluted in 15 mL saturated sodium bicarbonate. Theresulting solid was filtrated, washed with water, and dried to providecompound 185 as a yellow solid. ESI-MS m/z: 569.5 [M+H]⁺.

Example 154

Compound 186 was prepared in analogous fashion to compound 116 inExample 108 except that amine 141 was used in place of2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid. ESI-MS m/z: 546.5 [M+H]⁺.

Example 155

Compound 153 (0.03 mmol, 1.0 equiv) was dissolved in 3 mL methylenechloride and cooled to 0° C. Diisopropylethylamine (4.0 equiv) was addedfollowed by the addition of methylsulfonyl chloride (1.5 equiv) after 5min. The solution was slowly warmed to room temperature. After 1 h, nomore starting material remained by LC/MS. The mixture was concentratedand purified by HPLC (10-60% acetonitrile/0.1% formic acid in water) toprovide compound 187. ESI-MS m/z: 510.5 [M+H]⁺.

Example 156

Compound 188 was prepared according the Method A. It was then convertedto compound 189 in three steps in analogous fashion to compound 116 inExample 108. ESI-MS m/z: 550.5 [M+H]⁺.

Example 157

Compound 190 was prepared according to Method A. It was then convertedto compound 191 in analogous fashion to compound 70 in Example 63.ESI-MS m/z: 443.4 [M+H]⁺.

Example 158

A mixture of compound 63 (0.40 mmol, 1.0 equiv), potassiumcyclopropyltrifluoroborate (1.5 eq), Pd(amphos)₂Cl₂ (15 mol %) andsodium carbonate (2.0 equiv) in dioxane/water (4/1 v/v, 2 mL) wasdegassed with Ar for 10 min. The resulting mixture was heated to 85° C.and stirred for 120 h. The resulting suspension was cooled to RT,partitioned between methylene chloride and water. The aqueous layer wasextracted with methylene chloride (2×) and the combined organic layerswere dried with sodium sulfate, pre-adsorbed on silica gel and purifiedon silica gel column with ethyl acetate and hexanes to afford thecyclopropyl 192. ESI-MS m/z: 405.5 [M+H]⁺.

Compound 192 is converted to the compound 193 in three steps using theTFA deprotection conditions outlined in Example 63 followed by couplingand deprotection with 2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in analogous fashion tocompound 70 in Example 63. ESI-MS m/z: 465.3 [M+H]⁺.

Example 159

Compound 194 was prepared in analogous fashion to compound 183 inExample 151 except that (3-(N-cyclopropylsulfamoyl)phenyl)boronic acidwas used in place of (3-(methylsulfonamido)phenyl)boronic acid. ESI-MSm/z: 553.4 [M+H]⁺.

Example 160

Compound 195 was prepared according to Method H. It was then convertedto compound 196 in analogous fashion to compound 70 in Example 63.ESI-MS m/z: 465.3 [M+H]⁺.

Example 161

Compound 197 was prepared from 3-methylthiophene-2-carboxylic acid usingMethod A except that(S)—N-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)benzamide was used inplace of (S)-tert-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate Amine 197 was thenconverted to compound 198 in analogous fashion to compound 70 in Example63. ESI-MS m/z: 431.4 [M+H]⁺.

Example 162

Compound 70 (1.3 mmol, 1.0 equiv), trans-2-phenyl vinylboronic acid (1.8equiv) and Na₂CO₃ (2.0 equiv) were suspended in dioxane/water (4:1 v/v,240 mL). The suspension was bubbled with Ar for 5 min then charged withPd(amphos)Cl₂ (10 mol %). The mixture was bubbled with Ar for 8 minbefore it was heated to 95° C. in an oil bath for 2 h. After thereaction was determined complete by HPLC analysis, it was allowed tocool, diluted with ethyl acetate and water and transferred to aseparatory funnel. The organic layer was separated and the aqueous layerwas back extracted with ethyl acetate. The combined organic layers werewashed with brine, dried and concentrated to give crude material, whichwas purified by flash silica gel chromatography (ethyl acetate/hexanes)to provide compound 199. ESI-MS m/z: 527.5 [M+H]⁺.

Example 163

Compound 201 was prepared in 2 steps from compound 199 according to thefollowing procedure: Compound 199 (2.2 mmol, 1.0 equiv) in THF (50 mL),tert-butanol (25 mL), and water (10 mL) was treated with NMO (6.0 equiv)and OsO₄ solution (4%, 267 uL), after which the reaction was stirred atRT overnight, after which LC/MS analysis indicated conversion to diol200. The reaction mixture was concentrated under vacuum and added towater (50 mL) and saturated Na₂SO₃ (20 mL) and extracted with methylene(3×40 mL). The organic layers were washed with brine and concentrated toa yellow solid. This material was redissolved in THF (25 mL) and water(5 mL), then treated with NaIO₄ (4.0 equiv) and stirred at RT. After 1day, the major product was compound 201 by LC/MS analysis. The reactionmixture was diluted with methylene chloride and silica gel (10 g) wasadded. The mixture was concentrated and purified by flash silica gelchromatography (gradient: methylene chloride/acetone) to providealdehyde 201. ESI-MS m/z: 453.3 [M+H]⁺.

Example 164

Compound 202 was prepared in analogous fashion to compound 199 inExample 162 except that 3-acetamidophenyl boronic acid was used in placeof trans-2-phenyl vinyl boronic acid. ESI-MS m/z: 558.5 [M+H]⁺.

Example 165

Compound 203 was prepared in analogous fashion to compound 199 inExample 162 except that 4-acetamidophenyl boronic acid was used in placeof trans-2-phenyl vinyl boronic acid. ESI-MS m/z: 558.4 [M+H]⁺.

Example 166

A mixture of ethyl 4-hydroxy-2-methylthiophene-3-carboxylate 204 (5.56mmol, 1.0 equiv) and diisopropylethylamine (2.33 equiv) in methylene (20mL) was cooled to 15° C. Trifluoromethanesulfonic anhydride (1.88 equiv)was added and the resulting mixture was warmed up to RT and stirred for3 h. The mixture was then quenched with water (20 mL), the aqueous layerwas extracted with methylene chloride (2×) and the combined organiclayers were washed with brine, dried with sodium sulfate andconcentrated to dryness to afford compound 205. ESI-MS m/z: 319.2[M+H]⁺.

A mixture of compound 205 (5.05 mmol, 1.0 equiv),(1-methyl-1H-pyrazol-4-yl)boronic acid, pinacol ester (1.5 equiv),Pd(PPh₃)₄ (15 mol %) and sodium carbonate (2.0 eq) in dioxane/water (4/1v/v, 20 mL) was degassed with Ar for 10 min. The resulting mixture washeated to 85° C. and stirred for 18 h. The resulting suspension wascooled to RT, partioned between methylene chloride and water. Theaqueous layer was extracted with methylene chloride (2×) and thecombined organic layers were dried with sodium sulfate, pre-adsorbed onsilica gel and purified by flash silica gel chromatography (gradientacetone/methylene chloride) to afford compound 206. ESI-MS m/z: 251.3[M+H]⁺.

To a mixture of compound 206 (4.63 mmol, 1.0 equiv) in ethanol (10 mL)was added 20% aqueous NaOH (3.0 equiv). The resulting mixture was heatedto reflux and stirred for 1 h. The reaction mixture was cooled to RT andconcentrated. The residue was poured onto ice water (30 mL) andneutralized with concentrated HCl until pH 1-2. An off-white precipitatewas formed which was dissolved with methylene chloride. The mixture wastransferred to a separatory funnel and the aqueous layer was extractedwith methylene chloride (2×). The combined organic layers were washedwith brine, dried with sodium sulfate and concentrated to dryness toafford compound 207. ESI-MS m/z: 223.2 [M+H]⁺.

Compound 207 was then converted to compound 208 according the Method A.Amine 208 was then converted to compound 209 in analogous fashion tocompound 70 in example 63. MS m/z: 511.4 [M+H]⁺.

Example 167

A mixture of compound 205 (4.58 mmol, 1.0 equiv), pinacolborane (5.0equiv), Pd(dppf)Cl₂ (15 mol %) and triethylamine (3.0 equiv) in dioxane(30 mL) was degassed with Ar for 10 min. The resulting mixture washeated to reflux and stirred for 16.5 h. The reaction mixture wasquenched with water, the aqueous layer was extracted with methylenechloride (2×) after which the combined organic layers were dried withsodium sulfate and concentrated to dryness to afford compound 210.ESI-MS m/z: 297.3 [M+H]⁺.

A solution of compound 210 (4.58 mmol, 1.0 equiv) in methanol (20 mL)was then degassed with Ar for 5 min. Copper(II)chloride (3.0 eq) wasadded to the resulting solution and the mixture was heated to reflux andstirred for 1 h. The reaction mixture was then cooled to RT andconcentrated to dryness. The residue was partitioned between ethylacetate and water. The aqueous layer was extracted with ethyl acetate(2×), the combined organic layers were washed with brine, dried withsodium sulfate, pre-adsorbed on silica gel and purified using flashsilica gel chromatography (gradient: ethyl acetate/hexanes) to affordcompound 211. ESI-MS m/z: 205.2 [M+H]⁺.

Compound 211 was then converted to compound 212 using the analogousprocedure for compound 206 in Example 166. ESI-MS m/z: 465.2 [M+H]⁺.

Example 168

Compound 213 was prepared from compound 212 using the analogous couplingprocedure for compound 199 in Example 162 except that(2-methoxypyridin-4-yl)boronic acid was used in place of trans-2-phenylvinyl boronic acid. ESI-MS m/z: 538.3 [M+H]⁺.

Example 169

A mixture of 137 (0.028 mmol, 1.0 eq), morpholine (80 eq) anddiisopropylethylamine (4.0 eq) in NMP (4 mL) was degassed with Ar for 5min. The resulting mixture was sealed and heated in a microwave reactorto 150° C. for 17 h. The resulting suspension was cooled to RT,partitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate (2×) and the combined organic layers werewashed with brine, dried with sodium sulfate and concentrated todryness. The residue was dissolved in methanol and purified on semi-prepHPLC to afford the naphthyridine 214. ESI-MS m/z: 521.4 [M+H]⁺.

Example 170

Compound 215 was prepared according to WO 2008118468.

A mixture of chloride 215 (0.93 mmol, 1.0 equiv), phenylboronic acid(1.5 equiv), Pd(PPh₃)₄ (5 mol %) and sodium carbonate (2 equiv) indioxane/water (4/1 v/v, 65 mL) was then degassed with Ar for 10 min. Theresulting mixture was heated to 85° C. and stirred for 3 hr. Theresulting suspension was cooled to RT, partitioned between ethyl acetateand a saturated aqueous sodium chloride solution. The organic phase wasseparated, dried with sodium sulfate, pre-adsorbed on silica gel andpurified using silica gel chromatography with ethyl acetate and hexanesto afford compound 216. ESI-MS m/z: 413.3 [M+H]⁺.

A mixture of phtalimide 216 (0.56 mmol, 1.0 equiv) and hydrazine (20equiv) in methanol (10 mL) was heated to 75° C. and stirred for 1 hr.The resulting mixture was concentrated, re-suspended in methylenechloride and filtered. The filtrate was concentrated to dryness toafford compound 217. ESI-MS m/z: 283.3 [M+H]⁺.

Compound 217 was then converted to compound 218 in analogous fashion tocompound 70 in Example 63. ESI-MS m/z: 443.4 [M+H]⁺.

Example 171

Compound 218 (0.070 mmol, 1.0 equiv), (2-methoxypyridin-4-yl)boronicacid (2.0 equiv), and sodium carbonate (2.0 equiv) were suspended in 2mL dioxane/water (v/v 4:1) and bubbled with Ar for 10 min. Pd(amphos)Cl₂(5 mol %) was added and the reaction was heated to 85° C. for 1 h, afterwhich there was no starting material by LC/MS analysis. The reaction wasallowed to cool and transferred to a separatory funnel with excess waterand ethyl acetate. The organic layer was separated, dried over sodiumsulfate and concentrated under vacuum to provide crude residue, whichwas purified using flash silica gel chromatography (ISCO, gradient 0-20%acetone/methylene chloride) to provide compound 219. ESI-MS m/z: 516.4[M+H]⁺.

Example 172

Compound 220 was prepared in 3 steps from amine 182 in three steps inanalogous fashion to compound 116 in Example 108. ESI-MS m/z: 470.5[M+H]⁺.

The following compounds were prepared in analogous procedures to Example107, from the appropriate boronic acid and compound 1, followed by amideformation analogous to Example 63:

Example Compound Boronic Acid ESI-MS m/z 173

  221

491.4 [M + H]⁺ 174

  222

505.4 [M + H]⁺ 175

  223

532.5 [M + H]⁺

Example 176

Compound 224 was prepared from 2-methylthiophene-3-carboxylic acid usingMethod A except that(S)—N-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)benzamide was used inplace of (S)-tert-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate. It was thenconverted to compound 225 in analogous fashion to compound 70 in Example63. ESI-MS m/z: 431.4 [M+H]⁺.

Example 177

A mixture of aldehyde 201 (0.02 mmol, 1.0 equiv), hydroxylaminehydrochloride (1.5 equiv), and triethylamine (3.5 equiv) in 1 mLmethylene chloride and 1 mL methanol was stirred in a closed flask at25° C. for 3 h, at which point LC/MS analysis indicated completeconversion to the desired product. The solvent was evaporated and theresidue was purified by HPLC (10-60% acetonitrile/0.1% formic acid inwater) to provide compound 226. ESI-MS m/z: 468.4 [M+H]⁺.

Example 178

Hydroxylimine 226 (0.056 mmol, 1.0 equiv) in 2 mL dry methylene chloridewas added drop wise to a solution of benzotriazole (5.0 equiv) andthionyl chloride (5.0 equiv) in 2 mL dry methylene chloride. After firstfew drops, dark brown precipitate was formed. After the addition, theheterogeneous mixture was stirred at RT for 30 min, after which completeconversion of the starting material to product was observed by LC/MSanalysis. The mixture was then diluted with methylene chloride (40 mL)and transferred to a separatory funnel. The organic layer was thenwashed with sodium bicarbonate and brine, dried over sodium sulfate andconcentrated under vacuum. The crude product was purified by HPLC(10-60% acetonitrile/0.1% formic acid in water) to provide nitrile 227.ESI-MS m/z: 450.3 [M+H]⁺.

Example 179

Compound 201 (0.027 mmol, 1.0 equiv) was dissolved in 1.5 mL methanol.Sodium borohydride (2.0 equiv) was added and the reaction was allowed tostir at room temperature for 1 h. The reaction was then quenched withthe addition of 0.2 mL of water and purified by HPLC (10-60%acetonitrile/0.1% formic acid in water) to provide compound 228. ESI-MSm/z: 455.3 [M+H]⁺.

Example 180

Compound 201 (0.027 mmol, 1.0 equiv) was dissolved in 1.5 mL MeOH. R-THFamine (3.0 equiv) was added. Then sodium borohydride (2.0 equiv.) wasadded and stirred at room temperature for 1 h. The reaction was quenchedwith the addition of 0.2 mL water. The solution was purified by HPLC(10-60% acetonitrile/0.1% formic acid in water) to provide compound 229.ESI-MS m/z: 538.6 [M+H]⁺.

Example 181

Compound 201 (0.086 mmol, 1.0 equiv) was dissolved in 2 mL of methylenechloride. To this solution, methyl amine (0.086 ml, 2 M) was added. Thissolution was then stirred for 1 h, then sodium triacetoxyborohydride(2.0 equiv) was added, followed with acetic acid (10 equiv). After 2hours, there was no starting material by LC/MS analysis. The solvent wasremoved under reduced pressure and the crude material was purified byHPLC (10-60% acetonitrile/0.1% formic acid in water) to provide compound230. ESI-MS m/z: 468.1 [M+H]⁺.

Example 182

Compound 231 was prepared in analogous fashion to compound 230 inExample 181 except that dimethyl amine was used in place of methylamine. ESI-MS m/z: 482.1 [M+H]⁺.

Example 183

Compound 230 was coupled to acetic acid according to Method D to providecompound 232. ESI-MS m/z: 510.5 [M+H]⁺.

Example 184

Compound 233 was prepared from amine 195 in three steps in analogousfashion to compound 116 in Example 108. ESI-MS m/z: 538.6 [M+H]⁺.

Example 185

Compound 234 was prepared according the Method A. It was then convertedto compound 235 in analogous fashion to compound 70 in Example 63.ESI-MS m/z: 423.3 [M+H]⁺.

Example 186

Compound 236 was prepared from amine 234 and2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid according to method D. ESI-MS m/z: 523.5 [M+H]⁺.

A solution of 236 (0.96 mmol, 1.0 equiv) and N-methylmorpholine-N-oxide(2.0 equiv) in 12 mL THF, 5 mL tert-butanol and 5 mL water was treatedwith 4% osmium tetroxide in water (0.117 mL, 2 mol %). The mixture wasstirred for 26.5 h, and concentrated under reduced pressure. The cruderesidue was partitioned between 25 mL EtOAc and 5 mL water, and theaqueous layer was extracted with EtOAc (2×25 mL). The combined organiclayers were washed with 10 mL 2% sodium metabisulfite, 10 mL 2% citricacid, 20 mL water, and dried over sodium sulfate. The solvent wasevaporated under reduced pressure to give diol 237 as a 1:1 mixture ofdiasteromers. ESI-MS m/z: 557.4 [M+H]⁺.

A solution of 237 (0.048 mmol, equiv) in 0.5 mL anhydrous methylenechloride at 22° C. was treated with trifluoroacetic acid (15.0 equiv)and stirred for 2 h. The mixture was quenched with 4 mL 1 M NaOH,stirred for 15 min, and diluted with 5 mL methylene chloride. Theorganic layer was collected and the aqueous layer extracted withmethylene chloride (2×5 mL). The combined organic layers were washedwith 10 mL water, 10 mL brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give diol 238. ESI-MS m/z: 457.3[M+H]⁺.

Example 187

A solution of 237 (0.86 mmol, 1.0 equiv) in 10 mL THF and 6 mL water wastreated with sodium periodate (3.0 equiv) and stirred for 3 h. Themixture was then diluted with 30 mL THF. The remaining solids werefiltered and the filtrate was concentrated under reduced pressure. Theresidue was dissolved in 50 mL methylene chloride, washed with water(2×25 mL), 25 mL brine, dried over magnesium sulfate, and filtered. Thesolvents were evaporated under reduced pressure to provide aldehyde 239as a white solid. ESI-MS m/z: 525.0 [M+H]⁺.

Aldehyde 239 (0.095 mmol, 1.0 equiv) was dissolved in 1 mL 1:1methanol-THF and was treated with a solution of methyl amine in water(40%, 5.0 equiv) and sodium cyanoborohydride (2.0 equiv). The mixturewas treated with acetic acid (1.2 equiv) and the mixture was stirred atroom temperature for 18 h. The mixture was then diluted with 4 mLmethylene chloride and 4 mL water. The organic layer was collected; theaqueous layer was extracted with methylene chloride (3×5 mL). Thecombined organic layers were washed with 10 mL water, dried over sodiumsulfate, filtered and concentrated under reduced pressure to give thecrude amine 240. This compound was deprotected under analogostrifluoroacetic acid conditions for compound 238 in Example 186, andpurified using flash silica gel chromatography to provide compound 241.ESI-MS m/z: 440.3 [M+H]⁺.

Example 188

Compound 242 was prepared in analogous fashion as compound 241 inExample 187 except that dimethyl amine was used in place of methylamine. ESI-MS m/z: 454.3 [M+H]⁺.

Example 189

Compound 243 was prepared in analogous fashion as compound 241 inExample 187 except that ethanolamine was used in place of methyl amine.ESI-MS m/z: 470.3 [M+H]⁺.

Example 190

A mixture of 70 (0.33 mmol, 1.0 equiv), bis(pinacolato)diboron (3.0equiv), potassium acetate (3.0 equiv), Pd₂(dba)₃ (5 mol %) and XPhos (10mol %) were sequentially added into 4 mL dioxane previously degassedwith N₂ for 15 min. The mixture was stirred for 10 min at roomtemperature before heating at 100° C. for 2.5 h. The mixture was cooledto room temperature, diluted with 20 mL ethyl acetate followed by 20 mLwater, and transferred to a separatory funnel. The aqueous layer waswashed with 2×20 mL ethyl acetate (2×20 mL). The combined organic layerswere washed with water (2×20 mL) and brine (2×20 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure to give 429 mgof a mixture containing about 40% of 244. ESI-MS m/z: 551.2 [M+H]⁺.

The mixture containing 40% of 244 (0.036 mmol, 1 equiv) was to added to5-bromothiazole (0.22 mmol, 6.0 equiv), sodium carbonate (0.18 mmol, 5.0equiv) and Pd(dppf)₂Cl₂ (dichloromethane adduct, 10 mol %) in 2 mL 4:1(v/v) dioxane-water previously degassed with argon for 15 min. Themixture was stirred for 10 min at room temperature before heating at 88°C. for 2.5 h. The mixture was cooled to room temperature, diluted with10 mL methylene chloride followed by 10 mL water, and transferred to aseparatory funnel. The aqueous layer was extracted with methylenechloride (2×5 mL). The combined organic layers were washed with 2×10 mLwater (2×10 mL) and brine (2×10 mL), dried over sodium sulfate, filteredand concentrated under reduced pressure to give 70 mg of crude material,which was purified using flash silica gel chromatography (12 g, ISCO)using a gradient of 0-40% acetone/methylene to provide compound 245.ESI-MS m/z: 570.3 [M+H]⁺.

Example 191

Compound 246 was prepared from 244 using analogous procedures forcompound 245 in Example 190 except that 5-bromo-2-methoxythiazole wasused in place of 5-bromothiazole. ESI-MS m/z: 538.3 [M+H]⁺.

Example 192

Compound 247 was prepared from 244 using analogous procedures forcompound 245 in Example 190 except that N-(5-bromothiazol-2-yl)acetamidewas used in place of 5-bromothiazole. ESI-MS m/z: 565.3 [M+H]⁺.

Example 193

Compound 248 was prepared from 244 using analogous procedures forcompound 245 in Example 190 except that methyl5-bromothiazole-4-carboxylate was used in place of 5-bromothiazole.ESI-MS m/z: 566.4 [M+H]⁺.

Example 194

Amine 249 was prepared from 2-methylthiophene-3-carboxylic acid usingMethod A except that (S)-tert-butyl(1-(methoxy(methyl)amino)-1-oxobutan-2-yl)carbamate was used in place of(S)-tert-butyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate.Amine 249 was then converted to compound 250 in analogous fashion tocompound 70 in Example 63. ESI-MS m/z: 473.3 [M+H]⁺.

Example 195

A solution of amine 1 (3.35 mmol, 1.0 equiv) in methylene chloride (40mL) was cooled to 0° C. and charged with triethylamine (1.0 equiv) andtrifluoroacetic anhydride (1.0 equiv). The resulting mixture was stirredfor 15 min then partitioned between ethyl acetate and a saturatedaqueous sodium bicarbonate solution. The organic phase was separated,dried with sodium sulfate and concentrated to afford compound 251.ESI-MS m/z: 395.2 [M+H]⁺.

A solution of 251 (3.0 mmol, 1.0 equiv) in N,N-dimethylformamide (20 mL)was charged with N-bromosucciminide (1.0 equiv) and stirred at RT for 1hr. The resulting solution was charged with water (30 mL) and stirredfor 15 min. The resulting suspension was filtered, the cake washed withwater and air dried to constant weight to afford compound 252. ESI-MSm/z: 473.1 [M+H]⁺.

Compound 252 0.63 mmol, 1.0 equiv) and potassium carbonate (4.0 equiv)were dissolved in MeOH/water (10/1 v/v, 11 mL). The resulting solutionwas stirred at RT for 24 hr, and then was concentrated to dryness andpartitioned between methylene chloride and water. The organic phase wasseparated, dried with sodium sulfate and concentrated to afford compound253. ESI-MS m/z: 377.0 [M+H]⁺.

Compound 253 was the converted to compound 254 in analogous fashion tocompound 70 in Example 63. ESI-MS m/z: 537.2 [M+H]⁺.

Example 196

Compound 255 was prepared in analogous fashion to compound 254 inExample 195 except that amine 190 was used in place of compound 1.ESI-MS m/z: 521.1 [M+H]⁺.

Example 197

Compound 256 was isolated as a byproduct from the preparation ofcompound 254. ESI-MS m/z: 533.2 [M+H]⁺.

Example 198

Compound 257 was prepared in analogous fashion to compound 252 inExample 195.

A mixture of compound 257 (0.55 mmol, 1.0 equiv), methylboronic acid (2equiv), Pd(Amphos)Cl₂ (10 mol %) and sodium carbonate (2.5 equiv) indioxane/water (4/1 v/v, 3 mL) was degassed with Ar for 10 min. Theresulting mixture was heated to 90° C. and stirred for 3 hr. Theresulting suspension was cooled to RT, and partitioned between methyleneand water. The organic phase was separated, dried with sodium sulfateand concentrated. The residue was triturated with tert-butylmethylether,filtered and dried to constant weight to afford compound 258. ESI-MSm/z: 393.25 [M+H]⁺.

Compound 258 (0.47 mmol, 10 equiv) was dissolved in methanol (5 mL) andcharged with 6N aq. HCl (30 equiv). The resulting solution was stirredat 65° C. for 16 hr, and was then cooled to RT and concentrated todryness to provide amine 259 that was used directly in the next step.

Compound 259 was converted to compound 260 in analogous fashion tocompound 70 in Example 63. ESI-MS m/z: 457.4 [M+H]⁺.

Example 199

A solution of fluoride 260 (0.055 mmol, 1.0 equiv) in methanol (2 mL)was charged with 25% sodium methoxide (20 equiv), heated to 60° C. andstirred for 17 hr. The mixture was cooled to RT and partitioned betweenmethylene chloride and a saturated aqueous ammonium chloride solution.The organic phase was separated, dried with sodium sulfate andconcentrated. The residue was triturated in acetonitrile to affordcompound 261. ESI-MS m/z: 469.4 [M+H]⁺.

Example 200

A mixture of compound 15 (1.0 mmol, 1.0 eq), morpholine (66 eq) anddiisopropylethylamine (4.0 eq) was degassed with Ar for 5 min. Theresulting mixture was sealed and heated in a microwave reactor to 150°C. for 3 h. The resulting suspension was cooled to RT, partitionedbetween ethyl acetate and water. The aqueous layer was extracted withethyl acetate (2×). The combined organic layers were washed with brine,dried with sodium sulfate and concentrated to dryness to afford compound262. ESI-MS m/z: 549.3 [M+H]⁺.

Compound 262 was converted to 263 using analogous procedures forcompound 83 in Example 76. ESI-MS m/z: 640.4 [M+H]⁺.

Example 201

Compound 191 (0.057 mmol, 1.0 equiv) was dissolved in 0.5 mLN-methylpyrrolidone. Diisopropyl ethylamine (4.0 equiv) and N-methylpiperazine (10 equiv) were added and the mixture was sealed and heatedto 140° C. in a microwave reactor for 3 h, after which there was nostarting material by LC/MS analysis. The reaction was diluted with waterand methylene chloride (20 mL), and transferred to a separatory funnel.The organic layer was separated and concentrated. The crude material waspurified by flash silica gel chromatography (ISCO, 0-30%methanol/methylene chloride) to provide compound 264. ESI-MS m/z: 523.6[M+H]⁺.

The following compounds were prepared in analogous fashion:

Example Compound Amine ESI-MS m/z 202

  265

522.4 [M + H]⁺ 203

  266

454.4 [M + H]⁺ 204

  267

522.4 [M + H]⁺ 205

  268

482.4 [M + H]⁺

Example 206

A solution of compound 255 (0.093 mmol, 1.0 equiv) was dissolved inN,N-dimethylformamide (3 mL). Copper(I) cyanide (2.0 equiv) andcopper(I) iodide (0.7 equiv) were added and the mixture was degassedwith Ar for 10 min. Pd(amphos)Cl₂ (25 mol %) was then added and themixture was heated to 80° C. for 1 h, after which there was no startingmaterial by LC/MS analysis. The reaction was allowed to cool, and wasthen partitioned between brine and ethyl acetate in a separatory funnel.The combine organic layers were dried with sodium sulfate andconcentrated. The crude residue was purified by HPLC (10-60%methanol/0.1% trifluoroacetic acid in water) to provide compound 269.ESI-MS m/z: 468.3 [M+H]⁺.

Example 207

Compound 191 (0.054 mmol, 1.0 equiv) was suspended in methanol (1 mL)and charged with sodium methoxide (25% by weight in methanol, 80 equiv).The mixture was heated to 60° C. for 14 h, after which there was nostarting material left by LC/MS analysis. The reaction was thenpartitioned between methylene chloride and saturated ammonium chloridein a separatory funnel. The phases were separated and the aqueous layerwas back extracted with methylene chloride. The combined organic layerswere dried over sodium sulfate and concentrated to provide compound 270.ESI-MS m/z: 455.4 [M+H]⁺.

Example 208

Compound 271 was prepared from compound 244 using the analogousprocedure for compound 245 in Example 190 except that 2-bromothiophenewas used in place of 5-bromothiazole. ESI-MS m/z: 507.4 [M+H]⁺.

Example 209

Compound 272 was prepared from compound 240 in analogous fashion tocompound 187 in Example 155. It was then deprotected under standard TFAconditions to provide compound 273 as the desired sulfonamide. ESI-MSm/z: 518.3 [M+H]⁺.

Example 210

Amine 16 was prepared using Method A except that tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate was used in place of(S)-tert-butyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate.Amine 16 was then converted to compound 274 in analogous fashion tocompound 70 in Example 63. ESI-MS m/z: 445.3 [M+H]⁺.

Example 211

Compound 275 was prepared from compound 70 using analogous couplingconditions from Example 144. It was then converted to compound 276according to the following procedure: TBAF (1.0 M in tetrahydrofuran,1.4 equif) was added to compound 275 (0.077 mol, 1.0 equiv). Thereaction was allowed to stir overnight. The solvent was then removedunder vacuum and the crude residue was purified by flash silica gelchromatography to provide compound 276. ESI-MS m/z: 449.4 [M+H]⁺.

Example 212

Compound 286 was prepared according to the following procedures:

5-Methyl-3,4-dihydro-2H-pyrrole (120 mmol, 1.0 equiv) was added to asuspension of N-chlorosuccinamide (8.0 equiv) in tetrahydrofuran (300mL). The resulting mixture was heated to 55° C. and stirred for 35 min.The reaction mixture was cooled to RT and water (250 mL) was added. Theaqueous layer was extracted with hexanes (2×) and the combined organiclayers were concentrated to vacuum to afford compound 277.

A solution of compound 277 (120 mmol, 1.0 eq) in methanol (120 mL) wascooled to 0° C. and sodium methoxide in methanol (6.0 eq) was addeddropwise while keeping the temperature under 5° C. After the addition,the reaction mixture was warmed to RT and stirred for 2.5 hr. Thereaction mixture was acidified with 2N HCl and extracted with ethylacetate. The combined organic layers were washed with brine, dried withsodium sulfate and concentrated to dryness to afford compound 278.ESI-MS m/z: 160.0 [M+H]⁺.

A mixture of compound 278 (60 mmol, 1.0 eq) and 1N lithium hydroxide(4.0 eq) in methanol (30 mL) and tetrahydrofuran (30 mL) was stirred andheated to 60° C. for 1.5 hr. The reaction mixture was concentrated undervacuum. The residue was taken up with water and the resulting mixturewas acidified with 3N HCl (80 mL) until pH 1-2 to form an orangeprecipitate. The suspension was cooled to 0° C. and the precipitatefiltered to afford compound 279. ESI-MS m/z: 145.9 [M+H]⁺.

A mixture of compound 279 (50.2 mmol, 1.0 eq) and thionyl chloride (10eq) under Ar was heated to 75° C. for 50 min. The reaction mixture wascooled to RT and concentrated to dryness, and resuspended withtetrahydrofuran and then concentrated (3×). The residue was taken upwith dioxane and the resulting mixture was poured into a solution ofaniline (3.0 eq) in dioxane (400 mL) at 0° C. under Ar. The reactionmixture was stirred and heated to 60° C. for 2 hr. It was cooled to RTand concentrated to dryness. The residue was taken up with ethylacetate, washed with water, sodium bicarbonate, water, 2N HCl, water andbrine. The organic layer was dried with sodium sulfate and filtered. Theproduct was crashed out of solution with ethyl acetate and hexanes toafford compound 280. ESI-MS m/z: 221.2 [M+H]⁺.

To a mixture of 28% aq. sodium hydroxide (118 mL), 28% aq. ammoniumhydroxide (44 mL), ammonium chloride (6.0 eq), and Aliquat 336® (7 mol%) equipped with a mechanical stirrer was added a solution of compound280 (41 mmol, 1.0 eq) in methyl tert-butyl ether (320 mL) and ethylacetate (320 mL). The resulting mixture was cooled to 0° C. and 10% aq.sodium hypochlorite (11.0 eq) was added dropwise while keepingtemperature under 5° C. The resulting mixture was stirred at RT for 2.5hr. Solids were then dissolved with ethyl acetate (700 mL) and theorganic layer was washed with 25% aq. sodium thiosulfate (500 mL),water, and brine, dried with sodium sulfate and concentrated to dryness.The product was suspended in hexanes and filtered to afford compound281. ESI-MS m/z: 236.1 [M+H]⁺.

To a mixture of compound 281 (9.72 mmol, 1.0 eq),N-(t-butoxycarbonyl)-L-alanine (1.1 eq), hydroxybenzotriazole (1.0 eq)and 1-ethyl-3-(3-dimethylaminopropylpropyl)carbodiimide hydrochloride(1.1 eq) in N,N-dimethylformamide (60 mL) was addeddiisopropylethylamine (2.0 eq). The resulting mixture was stirred at RTfor 15 h after which an additional 0.6 equivalents ofN-(tert-butoxycarbonyl)-L-alanine and EDC were added. The reaction wasthen allowed to stir for an additional 50 h, after which it waspartitioned between ethyl acetate and sodium bicarbonate. The aqueouslayer was extracted with ethyl acetate and the combined organic layerswere washed with brine (3×), dried with sodium sulfate, pre-adsorbed onsilica gel and purified on silica gel column with acetone and methylenechloride to afford compound 282. ESI-MS m/z: 407.3 [M+H]⁺.

To a mixture of compound 282 (4.82 mmol, 1.0 eq), triphenylphosphine(5.0 eq), and iodine (4.9 eq) in anhydrous methylene chloride (200 mL)was added diisopropylethylamine (10.4 eq), and the resulting mixture wasstirred at RT for 1 hr. The reaction mixture was quenched with sodiumbicarbonate. The aqueous layer was extracted with methylene chloride(2×). The combined organic layers were washed with brine, dried oversodium sulfate, pre-adsorbed on silica gel and purified on silica gelcolumn with ethyl acetate, hexanes and 2% of triethylamine to affordcompound 283. ESI-MS m/z: 389.2 [M+H]⁺.

To a solution of compound 283 (0.705 mmol, 1.0 eq) in anhydrousmethylene chloride (6 mL) was added trifluoroacetic acid (60 equiv.) andthe reaction mixture was stirred at RT for 30 min. It was then quenchedwith sodium bicarbonate, and the aqueous layer was extracted withmethylene chloride (2×), and the combined organic layers were dried withsodium sulfate and concentrated to dryness to afford deprotected oxazineintermediate 284. This intermediate was pre-adsorbed on silica gel andpurified on silica gel column with acetone and methylene to affordcompound 285 which converts from the oxazine during purification. ESI-MSm/z: 289.1 [M+H]⁺.

Compound 285 was converted to compound 286 in analogous fashion tocompound 70 in Example 63. ESI-MS m/z: 449.3 [M+H]⁺.

Example 213

Compound 287 was prepared from compound 286 in analogous fashion tocompound 199 in Example 162 except that(1-methyl-1H-pyrazol-4-yl)boronic acid was used in place oftrans-2-phenyl vinylboronic acid. ESI-MS m/z: 495.3 [M+H]⁺.

Example 214

Compound 288 was prepared from coupling compound 253 and3-amino-5-methylpyrazine-2-carboxylic acid using Method D. ESI-MS m/z:514.1 [M+H]⁺.

Example 215

Compound 289 was prepared from coupling compound 143 and3-aminopyrazine-2-carboxylic acid using Method D. ESI-MS m/z: 421.3[M+H]⁺.

Example 216

Compound 296 was prepared according to the following procedures:

Amine 234 (6.7 mmol, 1.0 equiv) was suspended in methylene chloride (40mL). Sodium carbonate (2.0 equiv) was added and the reaction was stirredfor 5 min. Di-tert-butyl dicarbonate (1.1 equiv) was added and themixture was stirred at RT for 2.5 h, after which point there was nostarting material by LC/MS analysis. The reaction was transferred to aseparatory funnel with excess water and methylene chloride. The organiclayer was separated and the aqueous layer was extracted with methylenechloride (2×25 mL). The combined organic layers were washed with waterand brine, dried over sodium sulfate and concentrated to provide a crudemono-protected material. The mono-Boc-protected amine (0.59 mmol, 1.0equiv) and DMAP (2.5 equiv) were dissolved in tetrahydrofuran (10 mL).Di-tert-butyl-dicarbonate (2.2 equiv) was added and the mixture wasallowed to stir at room temperature for 72 h, after which there was nostarting material by LC/MS analysis. The reaction was partitionedbetween ethyl acetate and brine. The organic layer was dried with sodiumsulfate and concentrated under vacuum to provide a crude material thatwas purified using flash silica gel chromatography (ISCO, gradient ofethyl acetate/hexanes) to give compound 290.

Compound 290 was oxidized to diol 291 using the analogous procedure forcompound 237 in Example 186.

Diol 291 was converted to aldehyde 292 using the analogous procedure forcompound 239 in Example 187.

Aldehyde 292 (0.15 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (1.5 mL) and oxone (1.0 equiv). The reaction was stirred atroom temperature for 30 min. An additional 0.5 equivalents of oxone wasadded and the reaction was stirred at room temperature for an additional4.5 h, after which there was greater than 95% conversion by LC/MSanalysis. The reaction was then diluted with ethyl acetate (2 mL) andfiltered through a 1 μm acrodisc. The combined filtrates were acidifiedwith 10% citric acid (5 mL) and the aqueous layer was extracted withethyl acetate (3×5 mL). The combined organic layers were washed with 5%brine (4×5 mL) and saturated brine (1×). The organic layers were driedover sodium sulfate and concentrated to provide compound 293 which wasused directly in the next step.

Acid 293 was coupled to dimethyl amine using Method D to provide amide294.

Amide 294 was deprotected according to the following procedure: Compound294 (0.14 mmol, 1.0 equiv) was dissolved in methylene chloride (2 mL).Anisole (6.0 equiv) was added followed by trifluoroacetic acid (100equiv). The reaction was stirred for 1 h, after which there was nostarting material by LC/MS analysis. The solvent was evaporated toprovide crude 295 which was used directly in the next step.

Compound 295 was converted to compound 296 in analogous fashion tocompound 70 in Example 63 except that the final product was purified byflash silica gel chromatography (ISCO, gradient of acetone/methylenechloride with 1% methanol). ESI-MS m/z: 468.2 [M+H]⁺.

Example 217

3-Hydroxypyridine N-oxide (11 mmol, 10 equiv) was placed in a 500 mLflask followed by 100 mL of acetic anhydride. To this mixture, compound136 (1.1 mmol, 1.0 equiv) was added. The mixture was then heated toreflux. DMSO (2 mL) was added. After refluxing for 18 h, the mixture wascooled to RT. LC/MS analysis showed the desired product, along withother by-products. The reaction mixture was concentrated to removeacetic anhydride. To the resulting residue, methanol (4 mL) was added.The solution was purified by HPLC (10-60% acetonitrile/0.1% formic acidin water) to provide compound 297. This material was then cooled to 0°C. in a flask under N₂. Concentrated hydrosulfuric acid (5 mL) was addeddrop wise. The mixture was allowed to warm to RT and stirred for 2 h.Ice (10 g) was then added and the flask was placed in an ice bathAmmonia in water (10%) was added drop wise until the pH reached 10,after which solid precipitate formed. The solid was purified by flashsilica gel chromatography (ISCO, 10% acetone/methylene chloride) toprovide compound 298. ESI-MS m/z: 459.3 [M+H]⁺.

Example 218

2-Bromo-6-(trifluoromethoxy)benzoic acid (6.8 mmol) was dissolved inthionyl chloride (5 mL) and heated to 65° C. with stirring for 3 h. Theresulting solution was cooled to RT and concentrated under vacuum. Theresidue was then dissolved in methylene chloride (10 mL) and cooled to0° C. The resulting solution was charged with aniline (4.0 equiv) andstirred for 30 min. The mixture was warmed to RT and partitioned betweenmethylene chloride and water. The organic phase was separated, washedwith 1N aqueous HCl solution, dried with sodium sulfate and concentratedto afford compound 299. ESI-MS m/z: 360.2 [M+H]⁺.

A mixture of compound 299 (3.4 mmol), trimethylboroxine (10 equiv),Pd(PPh₃)₄ (10 mol %) and sodium carbonate (10 equiv) in dioxane/water(4/1 v/v, 60 mL) was degassed with Ar for 10 min. The resulting mixturewas heated to 85° C. and stirred for 18 h. The resulting suspension wascooled to RT and partitioned between ethyl acetate and a saturatedaqueous sodium chloride solution. The organic phase was separated, driedwith sodium sulfate, pre-adsorbed on silica gel and purified usingsilica gel chromatography with ethyl acetate and hexanes to affordcompound 300. ESI-MS m/z: 296.2 [M+H]⁺.

Compound 300 was converted to compound 301 using Method A. It was thenconverted to amide 302 in analogous fashion to compound 70 in Example63. ESI-MS m/z: 509.3 [M+H]⁺.

Example 219

Compound 190 (0.35 mmol) was dissolved in ethanol (6 mL) and Pd/C (5 mol%) was added. The reaction was stirred at RT under an atmosphere ofhydrogen. After 2 hr, there was no starting material by LC/MS analysis.The mixture was filtered through celite washing with excess ethanol, andconcentrated to provide amine 303 as a 9:1 mixture of diasteromers thatwas used directly in the next steps.

Compound 303 was converted to compound 304 in analogous fashion tocompound 70 in Example 63. ESI-MS m/z: 445.4 [M+H]⁺.

Example 220

Compound 305 was prepared by coupling amine 1 with2-amino-5-bromonicotinic acid according to Method D. It was then coupledwith 3-(N-methylsulfamoyl)phenyl boronic acid using similar procedurefor compound 83 in Example 76 to provide compound 306. ESI-MS m/z: 588.3[M+H]⁺.

Example 221

Compound 70 (40.0 mg, 0.087 mmol, 1.0 equiv.) was dissolved in 1 mL MeOHat 22° C. and treated with sodium borohydride (33.0 mg, 0.872 mmol, 10equiv.). The mixture was stirred for 20 h., filtered, diluted with 2 mLmethanol and purified by preparative HPLC using 20-80% ACN-water with0.1% formic acid to give 14.2 mg of 307. ESI-MS m/z 463.3 [M+H]⁺.

Biological Activity Assessment

TABLE 2 In Vitro IC₅₀ data for selected compounds. IC₅₀ ≧10 μM ≧1 μM &<10 μM ≧100 nM & <1 μM <100 nM PI3K α Compounds 19, 22, Compounds 4, 20,62, Compounds 77, 101, Compounds 127, 169, IC₅₀ 42, 45, 54, 55, 59, 71,65, 70, 72, 73, 74, 75, 107, 144, 157, 162, and 172. 80, 82, 88, 89, 90,91, 76, 78, 83, 85, 86, 87, 163, 164, 183, 194, 92, 94, 95, 96, 98, 93,97, 99, 100, 102, 273, and 276. 103, 104, 105, 106, 108, 109, 110, 112,111, 113, 121, 132, 115, 116, 117, 118, 133, 138, 139, 145, 119, 120,123, 128, 147, 148, 177, 178, 137, 140, 142, 150, 180, 184, 185, 193,152, 153, 154, 155, 198, 199, 201, 209, 156, 158, 159, 160, 213, 214,218, 219, 161, 165, 166, 167, 222, 223, 225, 226, 171, 186, 187, 189,227, 228, 229, 230, 191, 196, 202, 203, 231, 232, 233, 242, 212, 220,221, 235, 246, 248, 256, 261, 238, 241, 243, 245, 263, 264, 265, 267,247, 250, 254, 255, 268, 270, 274, 286, 260, 266, 269, and 287, 288,289, 296, 271, 298, 302, 304, 306, and 307. PI3K β Compounds 42, 54,Compounds 13, 20, Compounds 4, 19, 70, Compounds 74, 77, IC₅₀ 55, 59,80, 87, 88, 90, 22, 45, 62, 65, 71, 75, 72, 73, 76, 78, 83, 85, 107,127, 142, 169, 94, 95, 98, 103, 105, 82, 84, 86, 89, 91, 92, 97, 99,101, 102, 108, 172, 183, 194, 235, 106, 115, 117, 118, 93, 96, 100, 104,109, 111, 137, 152, 157, 238, 241, 242, 243, 119, 120, 121, 139, 110,112, 113, 116, 163, 171, 191, 212, and 250. 140, 148, 161, 177, 123,128, 132, 133, 260, 269, 273, and 180, 184, 185, 186, 138, 144, 145,147, 276. 189, 193, 199, 202, 150, 153, 154, 155, 203, 209, 213, 214,156, 158, 159, 160, 219, 220, 221, 222, 162, 164, 165, 166, 223, 226,229, 230, 167, 178, 187, 196, 231, 232, 233, 245, 198, 201, 218, 225,246, 247, 248, 256, 227, 228, 254, 255, 261, 263, 264, 265, 271, 289,296, and 266, 267, 268, 270, 298. 274, 286, 287, 288, 302, 304, 306, and307. PI3K δ Compounds 42, 80, Compounds 20, 22, Compounds 13, 19,Compounds 4, 55, 76, IC₅₀ 88, 90, 95, 103, 104, 54, 62, 65, 71, 72, 73,45, 59, 70, 74, 77, 78, 127, 172, 231, 232, 105, 106, 109, 112, 75, 82,83, 84, 85, 99, 107, 111, 118, 241, 242, 250, and 113, 132, 147, 177,86, 87, 89, 91, 92, 93, 119, 120, 121, 137, 289. 180, 184, 185, 199, 94,96, 97, 98, 100, 140, 142, 144, 155, 209, 213, 219, 233, 101, 102, 108,110, 156, 157, 169, 183, 248, 263, 264, 265, 115, 116, 117, 123, 191,194, 212, 235, 266, 267, 268, 274, 128, 133, 138, 139, 238, 243, 254,260, 286, 287, 296, 304, 145, 148, 150, 152, 269, 273, and 276. 306, and307. 153, 154, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 171,178, 186, 187, 189, 193, 196, 198, 201, 202, 203, 214, 218, 220, 221,222, 223, 225, 226, 227, 228, 229, 230, 245, 246, 247, 255, 256, 261,270, 271, 288, 298, and 302. PI3K γ Compounds 95, 105, Compounds 13, 20,Compounds 4, 19, 54, Compounds 70, 72, IC₅₀ 148, 177, 185, 199, 22, 42,45, 55, 59, 65, 62, 71, 73, 74, 77, 83, 75, 76, 78, 85, 99, 213, 230,231, 232, 80, 82, 88, 89, 90, 91, 84, 86, 87, 93, 97, 101, 102, 107,119, 264, 265, 268, 274, 92, 94, 96, 98, 100, 108, 110, 111, 112, 121,127, 140, 144, 286, 287, 296, 304, 103, 104, 106, 109, 115, 116, 117,118, 155, 156, 157, 158, 306, and 307. 113, 132, 139, 145, 120, 123,128, 133, 162, 163, 165, 167, 147, 150, 178, 180, 137, 138, 142, 152,169, 171, 172, 183, 184, 193, 196, 198, 153, 154, 159, 160, 191, 194,212, 254, 201, 209, 218, 219, 161, 164, 166, 186, 260, 273, and 276.220, 225, 229, 233, 187, 189, 202, 203, 241, 242, 243, 248, 214, 221,222, 223, 263, 266, 267, 270, 226, 227, 228, 235, 288, 298, and 302.238, 245, 246, 247, 250, 255, 256, 261, 269, 271, and 289. RAJI p110 δCompounds 88 and Compounds 68, 80, Compounds 13, 22, Compounds 4, 19,20, Assay IC₅₀ 106. 87, 90, 92, 103, 113, 42, 62, 75, 82, 84, 89, 45,54, 55, 59, 65, 67, 156, 180, 184, and 91, 93, 98, 104, 107, 70, 71, 72,73, 74, 76, 209. 108, 109, 112, 115, 77, 78, 83, 85, 86, 96, 132, 133,139, 150, 97, 99, 101, 102, 110, 153, 154, 166, 178, 111, 116, 117, 118,187, 189, 193, 198, 119, 120, 121, 123, 201, 219, 221, 225, 127, 128,137, 138, 228, 266, 267, 270, 140, 142, 144, 145, and 271. 152, 155,157, 158, 159, 160, 161, 162, 163, 164, 165, 167, 169, 171, 183, 186,191, 194, 196, 202, 203, 212, 214, 218, 220, 222, 223, 227, 235, 238,242, 245, 250, 254, 260, 269, 273, and 276. Raw264.7 p110 γ Compounds 14and Compounds 3, 42, 55, Compounds 13, 20, Compounds 4, 19, 45, AssayIC₅₀ 15. 59, 68, 88, and 92. 22, 54, 62, 80, 82, 87, 65, 67, 70, 71, 72,73, 89, 90, 91, 98, 103, 74, 75, 76, 77, 78, 83, 104, 106, 111, 113, 84,85, 86, 93, 96, 97, 120, 153, 154, 156, 99, 101, 102, 107, 166, 180,184, 198, 108, 109, 110, 112, 202, 209, 225, 242, 115, 116, 117, 118,267, and 270. 119, 121, 123, 127, 128, 132, 133, 137, 138, 139, 140,142, 144, 145, 150, 152, 155, 157, 158, 159, 160, 161, 162, 163, 164,165, 167, 169, 171, 178, 183, 186, 187, 189, 191, 193, 194, 196, 201,203, 212, 214, 218, 219, 220, 221, 222, 223, 227, 228, 235, 238, 245,250, 254, 260, 266, 269, 271, 273, and 276.

TABLE 3 Structures of the compounds for the IC₅₀ results describedherein. Structure

Compound 3

Compound 4

Compound 7

Compound 13

Compound 14

Compound 15

Compound 17

Compound 19

Compound 20

Compound 22

Compound 36

Compound 42

Compound 45

Compound 46

Compound 53

Compound 54

Compound 55

Compound 58

Compound 59

Compound 61

Compound 62

Compound 65

Compound 67

Compound 68

Compound 70

Compound 71

Compound 72

Compound 73

Compound 74

Compound 75

Compound 76

Compound 77

Compound 78

Compound 80

Compound 82

Compound 83

Compound 84

Compound 85

Compound 86

Compound 87

Compound 88

Compound 89

Compound 90

Compound 91

Compound 92

Compound 93

Compound 94

Compound 95

Compound 96

Compound 97

Compound 98

Compound 99

Compound 100

Compound 101

Compound 102

Compound 103

Compound 104

Compound 105

Compound 106

Compound 107

Compound 108

Compound 109

Compound 110

Compound 111

Compound 112

Compound 113

Compound 115

Compound 116

Compound 117

Compound 118

Compound 119

Compound 120

Compound 121

Compound 123

Compound 127

Compound 128

Compound 132

Compound 133

Compound 137

Compound 138

Compound 139

Compound 140

Compound 142

Compound 144

Compound 145

Compound 147

Compound 148

Compound 150

Compound 152

Compound 153

Compound 154

Compound 155

Compound 156

Compound 157

Compound 158

Compound 159

Compound 160

Compound 161

Compound 162

Compound 163

Compound 164

Compound 165

Compound 166

Compound 167

Compound 169

Compound 171

Compound 172

Compound 177

Compound 178

Compound 180

Compound 183

Compound 184

Compound 185

Compound 186

Compound 187

Compound 189

Compound 191

Compound 193

Compound 194

Compound 196

Compound 198

Compound 199

Compound 201

Compound 202

Compound 203

Compound 209

Compound 212

Compound 213

Compound 214

Compound 218

Compound 219

Compound 220

Compound 221

Compound 222

Compound 223

Compound 225

Compound 226

Compound 227

Compound 228

Compound 229

Compound 230

Compound 231

Compound 232

Compound 233

Compound 235

Compound 238

Compound 241

Compound 242

Compound 243

Compound 245

Compound 246

Compound 247

Compound 248

Compound 250

Compound 254

Compound 255

Compound 256

Compound 260

Compound 261

Compound 263

Compound 264

Compound 265

Compound 266

Compound 267

Compound 268

Compound 269

Compound 270

Compound 271

Compound 273

Compound 274

Compound 276

Compound 286

Compound 287

Compound 288

Compound 289

Compound 296

Compound 298

Compound 302

Compound 304

Compound 306

Example 222 PI3-Kinase HTRF™ Assay

A PI3-Kinase HTRF® assay kit (cat No. 33-016) purchased from MilliporeCorporation was used to screen compounds provided herein. This assayused specific, high affinity binding of the GRP1 pleckstrin homology(PH) domain to PIP3, the product of a Class 1A or 1B PI3 Kinase actingon its physiological substrate PIP2. During the detection phase of theassay, a complex was generated between the GST-tagged PH domain andbiotinylated short chain PIP3. The biotinylated PIP3 and the GST-taggedPH domain recruited fluorophores (Streptavidin-Allophycocyanin andEuropium-labeled anti-GST respectively) to form the fluorescenceresonance energy transfer (FRET) architecture, generating a stabletime-resolved FRET signal. The FRET complex was disrupted in acompetitive manner by non-biotinylated PIP3, a product formed in the PI3Kinase assay.

PI3 Kinase α, β, γ or δ activity was assayed using the PI3 Kinase HTRF®assay kit (catalogue No. 33-016) purchased from Millipore Corporation.Purified recombinant PI3Kα (catalogue No. 14-602-K), PI3Kβ (catalogueNo. 14-603-K), PI3Kγ (catalogue No. 14-558-K), and PI3Kδ (catalogue No.14-604-K) were obtained from Millipore Corporation. Purified recombinantPI3K enzyme was used to catalyze the phosphorylation ofphosphatidylinositol 4,5-bisphosphate (PIP2 at 10 μM) tophosphatidylinositol 3,4,5-trisphosphate (PIP3) in the presence of 10 μMATP. The assay was carried out in 384-well format and detected using aPerkin Elmer EnVision Xcite Multilabel Reader. Emission ratios wereconverted into percent inhibitions and imported into GraphPad Prismsoftware. The concentration necessary to achieve inhibition of enzymeactivity by 50% (IC₅₀) was calculated using concentrations ranging from20 μM to 0.1 nM (12-point curve). IC₅₀ values were determined using anonlinear regression model available in GraphPad Prism 5.

The following compounds were evaluated using the above Millipore assay:3, 4, 7, 13, 14, 15, 17, 19, 20, 22, 36, 42, 45, 46, 53, 54, 55, 58, 59,61, and 62. From this assay, it was found that the IC₅₀ values for thesecompounds for PI3K δ ranged from 81 nM to >20 μM, illustrating theeffectiveness of these compounds in inhibiting PI3K δ activity. Fromthis assay, it was found that the IC₅₀ values for these compounds forPI3K γ ranged from 8 nM to >20 μM, illustrating the effectiveness ofthese compounds in inhibiting PI3K γ activity. From this assay, it wasfound that the IC₅₀ values for these compounds for PI3K α ranged from 5μM to >20 μM, illustrating the effectiveness of these compounds ininhibiting PI3Kα activity. From this assay, it was found that the IC₅₀values for these compounds for PI3K β ranged from 410 nM to >20 μM,illustrating the effectiveness of these compounds in inhibiting PI3K βactivity.

Example 223 Chemical Stability

The chemical stability of one or more subject compounds is determinedaccording to standard procedures known in the art. The following detailsan exemplary procedure for ascertaining chemical stability of a subjectcompound. The default buffer used for the chemical stability assay isphosphate-buffered saline (PBS) at pH 7.4; other suitable buffers can beused. A subject compound is added from a 100 μM stock solution to analiquot of PBS (in duplicate) to give a final assay volume of 400 μL,containing 5 μM test compound and 1% DMSO (for half-life determination atotal sample volume of 700 μL is prepared). Reactions are incubated,with shaking, for 24 hours at 37° C.; for half-life determinationsamples are incubated for 0, 2, 4, 6, and 24 hours. Reactions arestopped by adding immediately 100 μL of the incubation mixture to 100 μLof acetonitrile and vortexing for 5 minutes. The samples are then storedat −20° C. until analysis by HPLC-MS/MS. Where desired, a controlcompound or a reference compound such as chlorambucil (5 μM) is testedsimultaneously with a subject compound of interest, as this compound islargely hydrolyzed over the course of 24 hours. Samples are analyzed via(RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLCconditions consist of a binary LC pump with autosampler, a mixed-mode,C12, 2×20 mm column, and a gradient program. Peak areas corresponding tothe analytes are recorded by HPLC-MS/MS. The ratio of the parentcompound remaining after 24 hours relative to the amount remaining attime zero, expressed as percent, is reported as chemical stability. Incase of half-life determination, the half-life is estimated from theslope of the initial linear range of the logarithmic curve of compoundremaining (%) vs. time, assuming first order kinetics.

Example 224 Expression and Inhibition Assays of p110α/p85α, p110β/p85α,p110δ/p85α, and p110γ

Class I PI3-Ks can be either purchased (p110α/p85α, p110β/p85α,p110δ/p85α from Upstate, and p110γ from Sigma) or expressed aspreviously described (Knight et al., 2004). IC₅₀ values are measuredusing either a standard TLC assay for lipid kinase activity (describedbelow) or a high-throughput membrane capture assay. Kinase reactions areperformed by preparing a reaction mixture containing kinase, inhibitor(2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mMMgCl₂), and freshly sonicated phosphatidylinositol (100 μg/ml).Reactions are initiated by the addition of ATP containing 10 μCi ofγ-32P-ATP to a final concentration of 10 or 100 μM and allowed toproceed for 5 minutes at room temperature. For TLC analysis, reactionsare then terminated by the addition of 105 μL 1N HCl followed by 160 μLCHCl₃:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged,and the organic phase is transferred to a new tube using a gel loadingpipette tip precoated with CHCl₃. This extract is spotted on TLC platesand developed for 3-4 hours in a 65:35 solution of n-propanol:1M aceticacid. The TLC plates are then dried, exposed to a phosphorimager screen(Storm, Amersham), and quantitated. For each compound, kinase activityis measured at 10-12 inhibitor concentrations representing two-folddilutions from the highest concentration tested (typically, 200 μM). Forcompounds showing significant activity, IC₅₀ determinations are repeatedtwo to four times, and the reported value is the average of theseindependent measurements.

Other commercial kits or systems for assaying PI3-K activities areavailable. The commercially available kits or systems can be used toscreen for inhibitors and/or agonists of PI3-Ks including, but notlimited to, PI 3-Kinase α, β, δ, and γ. An exemplary system is PI3-Kinase (human) HTRF™ Assay from Upstate. The assay can be carried outaccording to the procedures suggested by the manufacturer. Briefly, theassay is a time resolved FRET assay that indirectly measures PIP3product formed by the activity of a PI3-K. The kinase reaction isperformed in a microtiter plate (e.g., a 384 well microtiter plate). Thetotal reaction volume is approximately 20 μL per well. In the firststep, each well receives 2 μL of test compound in 20% dimethylsulphoxideresulting in a 2% DMSO final concentration. Next, approximately 14.5 μLof a kinase/PIP2 mixture (diluted in 1× reaction buffer) is added perwell for a final concentration of 0.25-0.3 μg/mL kinase and 10 μM PIP2.The plate is sealed and incubated for 15 minutes at room temperature. Tostart the reaction, 3.5 μL of ATP (diluted in 1× reaction buffer) isadded per well for a final concentration of 10 μM ATP. The plate issealed and incubated for 1 hour at room temperature. The reaction isstopped by adding 5 μL of Stop Solution per well and then 5 μL ofDetection Mix is added per well. The plate is sealed, incubated for 1hour at room temperature, and then read on an appropriate plate reader.Data is analyzed and IC₅₀s are generated using GraphPad Prism 5.

Example 225 B Cell Activation and Proliferation Assay

The ability of one or more subject compounds to inhibit B cellactivation and proliferation is determined according to standardprocedures known in the art. For example, an in vitro cellularproliferation assay is established that measures the metabolic activityof live cells. The assay is performed in a 96 well microtiter plateusing Alamar Blue reduction. Balb/c splenic B cells are purified over aFicoll-Paque™ PLUS gradient followed by magnetic cell separation using aMACS B cell Isolation Kit (Miletenyi). Cells are plated in 90 μL at50,000 cells/well in B Cell Media (RPMI+10% FBS+Penn/Strep+50 μM bME+5mM HEPES). A compound provided herein is diluted in B Cell Media andadded in a 10 μL volume. Plates are incubated for 30 min at 37° C. and5% CO₂ (0.2% DMSO final concentration). A 50 μL B cell stimulationcocktail is then added containing either 10 μg/mL LPS or 5 μg/mL F(ab′)2Donkey anti-mouse IgM plus 2 ng/mL recombinant mouse IL4 in B CellMedia. Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volumeof 15 μL of Alamar Blue reagent is added to each well and plates areincubated for 5 hours at 37° C. and 5% CO₂. Alamar Blue fluoresce isread at 560Ex/590Em, and IC₅₀ or EC₅₀ values are calculated usingGraphPad Prism 5.

Example 226 Tumor Cell Line Proliferation Assay

The ability of one or more subject compounds to inhibit tumor cell lineproliferation can be determined according to standard procedures knownin the art. For instance, an in vitro cellular proliferation assay canbe performed to measure the metabolic activity of live cells. The assayis performed in a 96-well microtiter plate using Alamar Blue reduction.Human tumor cell lines are obtained from ATCC (e.g., MCF7, U-87 MG,MDA-MB-468, PC-3), grown to confluency in T75 flasks, trypsinized with0.25% trypsin, washed one time with Tumor Cell Media (DMEM+10% FBS), andplated in 90 μL at 5,000 cells/well in Tumor Cell Media. A compoundprovided herein is diluted in Tumor Cell Media and added in a 10 μLvolume. Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volumeof 10 μL of Alamar Blue reagent is added to each well and plates areincubated for 3 hours at 37° C. and 5% CO₂. Alamar Blue fluoresce isread at 560Ex/590Em, and IC₅₀ values are calculated using GraphPad Prism5.

Example 227 Antitumor Activity In Vivo

The compounds described herein can be evaluated in a panel of human andmurine tumor models.

Paclitaxel-Refractory Tumor Models

1. Clinically-Derived Ovarian Carcinoma Model.

This tumor model is established from a tumor biopsy of an ovarian cancerpatient. Tumor biopsy is taken from the patient. The compounds describedherein are administered to nude mice bearing staged tumors using anevery 2 days×5 schedule.

2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).

A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It isderived from the sensitive parent A2780 line by co-incubation of cellswith paclitaxel and verapamil, an MDR-reversal agent. Its resistancemechanism has been shown to be non-MDR related and is attributed to amutation in the gene encoding the beta-tubulin protein. The compoundsdescribed herein can be administered to mice bearing staged tumors on anevery 2 days×5 schedule.

3. HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug Resistant).

HCT116/VM46 is an MDR-resistant colon carcinoma developed from thesensitive HCT116 parent line. In vivo, grown in nude mice, HCT116/VM46has consistently demonstrated high resistance to paclitaxel. Thecompounds described herein can be administered to mice bearing stagedtumors on an every 2 days×5 schedule.

4. M5076 Murine Sarcoma Model

M5076 is a mouse fibrosarcoma that is inherently refractory topaclitaxel in vivo. The compounds described herein can be administeredto mice bearing staged tumors on an every 2 days×5 schedule.

One or more compounds as provided herein can be used in combination withother therapeutic agents in vivo in the multidrug resistant human coloncarcinoma xenografts HCT/VM46 or any other model known in the artincluding those described herein.

Example 228 Microsome Stability Assay

The stability of one or more subject compounds is determined accordingto standard procedures known in the art. For example, stability of oneor more subject compounds is established by an in vitro assay. Forexample, an in vitro microsome stability assay is established thatmeasures stability of one or more subject compounds when reacting withmouse, rat or human microsomes from liver. The microsome reaction withcompounds is performed in 1.5 mL Eppendorf tube. Each tube contains 0.1μL of 10.0 mg/mL NADPH; 75 μL of 20.0 mg/mL mouse, rat or human livermicrosome; 0.4 μL of 0.2 M phosphate buffer, and 425 μL of ddH₂O,Negative control (without NADPH) tube contains 75 μL of 20.0 mg/mLmouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer,and 525 μL of ddH₂O. The reaction is started by adding 1.0 μL of 10.0 mMtested compound. The reaction tubes are incubated at 37° C. 100 μLsample is collected into new Eppendorf tube containing 300 μL coldmethanol at 0, 5, 10, 15, 30 and 60 minutes of reaction. Samples arecentrifuged at 15,000 rpm to remove protein. Supernatant of centrifugedsample is transferred to new tube. Concentration of stable compoundafter reaction with microsome in the supernatant is measured by LiquidChromatography/Mass Spectrometry (LC-MS).

Example 229 Plasma Stability Assay

The stability of one or more subject compounds in plasma is determinedaccording to standard procedures known in the art. See, e.g., RapidCommun. Mass Spectrom., 10: 1019-1026. The following procedure is anHPLC-MS/MS assay using human plasma; other species including monkey,dog, rat, and mouse are also available. Frozen, heparinized human plasmais thawed in a cold water bath and spun for 10 minutes at 2000 rpm at 4°C. prior to use. A subject compound is added from a 400 μM stocksolution to an aliquot of pre-warmed plasma to give a final assay volumeof 400 μL (or 800 μL for half-life determination), containing 5 μM testcompound and 0.5% DMSO. Reactions are incubated, with shaking, for 0minutes and 60 minutes at 37 C, or for 0, 15, 30, 45 and 60 minutes at37 C for half life determination. Reactions are stopped by transferring50 μL of the incubation mixture to 200 μL of ice-cold acetonitrile andmixed by shaking for 5 minutes. The samples are centrifuged at 6000×gfor 15 minutes at 4° C. and 120 μL of supernatant removed into cleantubes. The samples are then evaporated to dryness and submitted foranalysis by HPLC-MS/MS.

In one embodiment, one or more control or reference compounds (5 μM) aretested simultaneously with the test compounds: one compound,propoxycaine, with low plasma stability and another compound,propantheline, with intermediate plasma stability.

Samples are reconstituted in acetonitrile/methanol/water (1/1/2, v/v/v)and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring(SRM). The HPLC conditions consist of a binary LC pump with autosampler,a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areascorresponding to the analytes are recorded by HPLC-MS/MS. The ratio ofthe parent compound remaining after 60 minutes relative to the amountremaining at time zero, expressed as percent, is reported as plasmastability. In case of half-life determination, the half-life isestimated from the slope of the initial linear range of the logarithmiccurve of compound remaining (%) vs. time, assuming first order kinetics.

Example 230 Kinase Signaling in Blood

PI3K/Akt/mTOR signaling is measured in blood cells using the phosflowmethod (Methods Enzymol. (2007) 434:131-54). This method is by nature asingle cell assay so that cellular heterogeneity can be detected ratherthan population averages. This allows concurrent distinction ofsignaling states in different populations defined by other markers.Phosflow is also highly quantitative. To test the effects of one or morecompounds provided herein, unfractionated splenocytes, or peripheralblood mononuclear cells are stimulated with anti-CD3 to initiate T-cellreceptor signaling. The cells are then fixed and stained for surfacemarkers and intracellular phosphoproteins Inhibitors provided hereininhibit anti-CD3 mediated phosphorylation of Akt-S473 and S6, whereasrapamycin inhibits S6 phosphorylation and enhances Akt phosphorylationunder the conditions tested.

Similarly, aliquots of whole blood are incubated for 15 minutes withvehicle (e.g., 0.1% DMSO) or kinase inhibitors at variousconcentrations, before addition of stimuli to crosslink the T cellreceptor (TCR) (anti-CD3 with secondary antibody) or the B cell receptor(BCR) using anti-kappa light chain antibody (Fab′2 fragments). Afterapproximately 5 and 15 minutes, samples are fixed (e.g., with cold 4%paraformaldehyde) and used for phosflow. Surface staining is used todistinguish T and B cells using antibodies directed to cell surfacemarkers that are known to the art. The level of phosphorylation ofkinase substrates such as Akt and S6 are then measured by incubating thefixed cells with labeled antibodies specific to the phosphorylatedisoforms of these proteins. The population of cells are then analyzed byflow cytometry.

Example 231 Colony Formation Assay

Murine bone marrow cells freshly transformed with a p190 BCR-Ablretrovirus (herein referred to as p190 transduced cells) are plated inthe presence of various drug combinations in M3630 methylcellulose mediafor about 7 days with recombinant human IL-7 in about 30% serum, and thenumber of colonies formed is counted by visual examination under amicroscope.

Alternatively, human peripheral blood mononuclear cells are obtainedfrom Philadelphia chromosome positive (Ph+) and negative (Ph−) patientsupon initial diagnosis or relapse. Live cells are isolated and enrichedfor CD19+ CD34+ B cell progenitors. After overnight liquid culture,cells are plated in methocult GF+ H4435 (Stem Cell Technologies),supplemented with cytokines (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3ligand, and erythropoietin) and various concentrations of knownchemotherapeutic agents in combination with compounds of the presentdisclosure. Colonies are counted by microscopy 12-14 days later. Thismethod can be used to test for evidence of additive or synergisticactivity.

Example 232 In Vivo Effect of Kinase Inhibitors on Leukemic Cells

Female recipient mice are lethally irradiated from a γ source in twodoses about 4 hr apart, with approximately 5Gy each. About 1 hr afterthe second radiation dose, mice are injected i.v. with about 1×10⁶leukemic cells (e.g., Ph+ human or murine cells, or p190 transduced bonemarrow cells). These cells are administered together with aradioprotective dose of about 5×10⁶ normal bone marrow cells from 3-5week old donor mice. Recipients are given antibiotics in the water andmonitored daily. Mice who become sick after about 14 days are euthanizedand lymphoid organs are harvested for analysis. Kinase inhibitortreatment begins about 10 days after leukemic cell injection andcontinues daily until the mice become sick or a maximum of approximately35 days post-transplant. Inhibitors are given by oral lavage.

Peripheral blood cells are collected approximately on day 10(pre-treatment) and upon euthanization (post treatment), contacted withlabeled anti-hCD4 antibodies and counted by flow cytometry. This methodcan be used to demonstrate that the synergistic effect of one or morecompounds provided herein in combination with known chemotherapeuticagents can reduce leukemic blood cell counts as compared to treatmentwith known chemotherapeutic agents (e.g., Gleevec) alone under theconditions tested.

Example 233 Treatment of Lupus Disease Model Mice

Mice lacking the inhibitory receptor FcγRIIb that opposes PI3K signalingin B cells develop lupus with high penetrance. FcγRIIb knockout mice(R2KO, Jackson Labs) are considered a valid model of the human diseaseas some lupus patients show decreased expression or function of FcγRIIb(S. Bolland and J. V. Ravtech 2000. Immunity 12:277-285).

The R2KO mice develop lupus-like disease with anti-nuclear antibodies,glomerulonephritis and proteinurea within about 4-6 months of age. Forthese experiments, the rapamycin analogue RAD001 (available from LCLaboratories) is used as a benchmark compound, and administered orally.This compound has been shown to ameliorate lupus symptoms in theB6.Sle1z.Sle3z model (T. Wu et al. J. Clin Invest. 117:2186-2196).

The NZB/W F1 mice spontaneously develop a systemic autoimmune diseasewith that is a model of lupus. The mice are treated starting at 20 weeksof age for a profilactic model and at 23 weeks of age for a therapeuticmodel. Blood and urine samples are obtained throughout the testingperiod, and tested for antinuclear antibodies (in dilutions of serum) orprotein concentration (in urine). Serum is also tested for anti-ssDNAand anti-dsDNA antibodies by ELISA. Glomerulonephritis is assessed inkidney sections stained with H&E at the end of the study, or survivalcan be an endpoint. For example, the proteozome inhibitor Bortezimib iseffective at blocking disease in the NZB/W model in both the profilacticand therapeutic model with reductions in auto-antibody production,kidney damage, and improvements in survival (Nature Medicine 14, 748-755(2008)).

Lupus disease model mice such as R2KO, BXSB or MLR/lpr are treated atabout 2 months old, approximately for about two months. Mice are givendoses of: vehicle, RAD001 at about 10 mg/kg, or compounds providedherein at approximately 1 mg/kg to about 500 mg/kg. Blood and urinesamples are obtained throughout the testing period, and tested forantinuclear antibodies (in dilutions of serum) or protein concentration(in urine). Serum is also tested for anti-ssDNA and anti-dsDNAantibodies by ELISA. Animals are euthanized at day 60 and tissuesharvested for measuring spleen weight and kidney disease.Glomerulonephritis is assessed in kidney sections stained with H&E.Other animals are studied for about two months after cessation oftreatment, using the same endpoints.

This established art model can be employed to demonstrate that thekinase inhibitors provided herein can suppress or delay the onset oflupus symptoms in lupus disease model mice.

Example 234 Murine Bone Marrow Transplant Assay

Female recipient mice are lethally irradiated from a γ ray source. About1 hr after the radiation dose, mice are injected with about 1×106leukemic cells from early passage p190 transduced cultures (e.g., asdescribed in Cancer Genet Cytogenet. 2005 August; 161(1):51-6). Thesecells are administered together with a radioprotective dose ofapproximately 5×10⁶ normal bone marrow cells from 3-5 wk old donor mice.Recipients are given antibiotics in the water and monitored daily. Micewho become sick after about 14 days are euthanized and lymphoid organsharvested for flow cytometry and/or magnetic enrichment. Treatmentbegins on approximately day 10 and continues daily until mice becomesick, or after a maximum of about 35 days post-transplant. Drugs aregiven by oral gavage (p.o.). In a pilot experiment, a dose ofchemotherapeutic that is not curative but delays leukemia onset by aboutone week or less is identified; controls are vehicle-treated or treatedwith chemotherapeutic agent, previously shown to delay but not cureleukemogenesis in this model (e.g., imatinib at about 70 mg/kg twicedaily). For the first phase, p190 cells that express eGFP are used, andpostmortem analysis is limited to enumeration of the percentage ofleukemic cells in bone marrow, spleen and lymph node (LN) by flowcytometry. In the second phase, p190 cells that express a tailless formof human CD4 are used and the postmortem analysis includes magneticsorting of hCD4+ cells from spleen followed by immunoblot analysis ofkey signaling endpoints: p Akt-T308 and S473; pS6 and p4EBP-1. Ascontrols for immunoblot detection, sorted cells are incubated in thepresence or absence of kinase inhibitors of the present disclosureinhibitors before lysis. Optionally, “phosflow” is used to detect pAkt-S473 and pS6-S235/236 in hCD4-gated cells without prior sorting.These signaling studies are particularly useful if, for example,drug-treated mice have not developed clinical leukemia at the 35 daytime point. Kaplan-Meier plots of survival are generated and statisticalanalysis done according to methods known in the art. Results from p190cells are analyzed separated as well as cumulatively.

Samples of peripheral blood (100-200 μL) are obtained weekly from allmice, starting on day 10 immediately prior to commencing treatment.Plasma is used for measuring drug concentrations, and cells are analyzedfor leukemia markers (eGFP or hCD4) and signaling biomarkers asdescribed herein.

This general assay known in the art can be used to demonstrate thateffective therapeutic doses of the compounds provided herein can be usedfor inhibiting the proliferation of leukemic cells.

Example 235 Matrigel Plug Angiogenesis Assay

Matrigel containing test compounds are injected subcutaneously orintraocularly, where it solidifies to form a plug. The plug is recoveredafter 7-21 days in the animal and examined histologically to determinethe extent to which blood vessels have entered it. Angiogenesis ismeasured by quantification of the vessels in histologic sections.Alternatively, fluorescence measurement of plasma volume is performedusing fluorescein isothiocyanate (FITC)-labeled dextran 150. The resultsare expected to indicate one or more compounds provided herein thatinhibit angiogenesis and are thus expected to be useful in treatingocular disorders related to aberrant angiogenesis and/or vascularpermeability.

Example 236 Corneal Angiogenesis Assay

A pocket is made in the cornea, and a plug containing an angiogenesisinducing formulation (e.g., VEGF, FGF, or tumor cells), when introducedinto this pocket, elicits the ingrowth of new vessels from theperipheral limbal vasculature. Slow-release materials such as ELVAX(ethylene vinyl copolymer) or Hydron are used to introduce angiogenesisinducing substances into the corneal pocket. Alternatively, a spongematerial is used.

The effect of putative inhibitors on the locally induced (e.g., spongeimplant) angiogenic reaction in the cornea (e.g., by FGF, VEGF, or tumorcells). The test compound is administered orally, systemically, ordirectly to the eye. Systemic administration is by bolus injection or,more effectively, by use of a sustained-release method such asimplantation of osmotic pumps loaded with the test inhibitor.Administration to the eye is by any of the methods described hereinincluding, but not limited to eye drops, topical administration of acream, emulsion, or gel, intravitreal injection.

The vascular response is monitored by direct observation throughout thecourse of the experiment using a stereomicroscope in mice. Definitivevisualization of the corneal vasculature is achieved by administrationof fluorochrome-labeled high-molecular weight dextran. Quantification isperformed by measuring the area of vessel penetration, the progress ofvessels toward the angiogenic stimulus over time, or in the case offluorescence, histogram analysis or pixel counts above a specific(background) threshold.

The results can indicate one or more compounds provided herein inhibitangiogenesis and thus can be useful in treating ocular disorders relatedto aberrant angiogenesis and/or vascular permeability.

Example 237 Microtiter-Plate Angiogenesis Assay

The assay plate is prepared by placing a collagen plug in the bottom ofeach well with 5-10 cell spheroids per collagen plug each spheroidcontaining 400-500 cells. Each collagen plug is covered with 1100 μL ofstorage medium per well and stored for future use (1-3 days at 37° C.,5% CO₂). The plate is sealed with sealing. Test compounds are dissolvedin 200 μL assay medium with at least one well including a VEGF positivecontrol and at least one well without VEGF or test compound as anegative control. The assay plate is removed from the incubator andstorage medium is carefully pipeted away. Assay medium containing thetest compounds are pipeted onto the collagen plug. The plug is placed ina humidified incubator for (37° C., 5% CO₂) 24-48 hours. Angiogenesis isquantified by counting the number of sprouts, measuring average sproutlength, or determining cumulative sprout length. The assay can bepreserved for later analysis by removing the assay medium, adding 1 mLof 10% paraformaldehyde in Hanks BSS per well, and storing at 4° C. Theresults are expected to identify compounds that inhibit angiogenesis invarious cell types tested, including cells of ocular origin.

Example 238 Combination Use of PI3K-δ Inhibitors and Agents that InhibitIgE Production or Activity

The compounds as provided herein can present synergistic or additiveefficacy when administered in combination with agents that inhibit IgEproduction or activity. Agents that inhibit IgE production include, forexample, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as Omalizumab and TNX-901.

One or more of the subject compounds capable of inhibiting PI3K-δ can beefficacious in treatment of autoimmune and inflammatory disorders(AIID), for example, rheumatoid arthritis. If any of the compoundscauses an undesired level of IgE production, one can choose toadminister it in combination with an agent that inhibits IgE productionor IgE activity. Additionally, the administration of PI3K-δ or PI3K-δ/γinhibitors as provided herein in combination with inhibitors of mTOR canalso exhibit synergy through enhanced inhibition of the PI3K pathway.Various in vivo and in vitro models can be used to establish the effectof such combination treatment on AIID including, but not limited to: (a)in vitro B-cell antibody production assay, (b) in vivo TNP assay, and(c) rodent collagen induced arthritis model.

(a) B-Cell Assay

Mice are euthanized, and the spleens are removed and dispersed through anylon mesh to generate a single-cell suspension. The splenocytes arewashed (following removal of erythrocytes by osmotic shock) andincubated with anti-CD43 and anti-Mac-1 antibody-conjugated microbeads(Miltenyi Biotec). The bead-bound cells are separated from unbound cellsusing a magnetic cell sorter. The magnetized column retains the unwantedcells and the resting B cells are collected in the flow-through.Purified B-cells are stimulated with lipopolysaccharide or an anti-CD40antibody and interleukin 4. Stimulated B-cells are treated with vehiclealone or with PI3K-δ inhibitors as provided herein with and without mTORinhibitors such as rapamycin, rapalogs, or mTORC1/C2 inhibitors. Theresults are expected to show that in the presence of mTOR inhibitors(e.g., rapamycin) alone, there is little to no substantial effect on IgGand IgE response. However, in the presence of PI3K-δ and mTORinhibitors, the B-cells are expected to exhibit a decreased IgG responseas compared to the B-cells treated with vehicle alone, and the B-cellsare expected to exhibit a decreased IgE response as compared to theresponse from B-cells treated with PI3K-δ inhibitors alone.

(b) TNP Assay

Mice are immunized with TNP-Ficoll or TNP-KHL and treated with: vehicle,a PI3K-δ inhibitor, an mTOR inhibitor, for example rapamycin, or aPI3K-δ inhibitor in combination with an mTOR inhibitor such asrapamycin. Antigen-specific serum IgE is measured by ELISA using TNP-BSAcoated plates and isotype specific labeled antibodies. It is expectedthat mice treated with an mTOR inhibitor alone exhibit little or nosubstantial effect on antigen specific IgG3 response and nostatistically significant elevation in IgE response as compared to thevehicle control. It is also expected that mice treated with both PI3K-δinhibitor and mTOR inhibitor exhibit a reduction in antigen specificIgG3 response as compared to the mice treated with vehicle alone.Additionally, the mice treated with both PI3K-δ inhibitor and mTORinhibitor exhibit a decrease in IgE response as compared to the micetreated with PI3K-δ inhibitor alone.

(c) Rat Collagen Induced Arthritis Model

Female Lewis rats are anesthetized and given collagen injectionsprepared and administered as described previously on day 0. On day 6,animals are anesthetized and given a second collagen injection. Calipermeasurements of normal (pre-disease) right and left ankle joints areperformed on day 9. On days 10-11, arthritis typically occurs and ratsare randomized into treatment groups. Randomization is performed afterankle joint swelling is obviously established and there is good evidenceof bilateral disease.

After an animal is selected for enrollment in the study, treatment isinitiated. Animals are given vehicle, PI3K-δ inhibitor, or PI3K-δinhibitor in combination with rapamycin. Dosing is administered on days1-6. Rats are weighed on days 1-7 following establishment of arthritisand caliper measurements of ankles taken every day. Final body weightsare taken on day 7 and animals are euthanized.

The combination treatment using a compound as provided herein andrapamycin can provide greater efficacy than treatment with PI3K-δinhibitor alone.

Example 239 Delayed Type Hypersensitivity Model

DTH is induced by sensitizing 60 BALB/c male mice on day 0 and day 1with a solution of 0.05% 2,4 dinitrofluorobenzene (DNFB) in a 4:1acetone/olive oil mixture. Mice are gently restrained while 20 μL ofsolution is applied to the hind foot pads of each mouse. The hind footpads of the mice are used as they represent an anatomical site that canbe easily isolated and immobilized without anesthesia. On day 5, miceare administered a single dose of vehicle, a compound provided herein at10, 3, 1, or 0.3 mg/kg, or dexamethasone at a dose of 5 mg/kg by oralgavage. Thirty minutes later mice are anaesthetized, and a solution of0.25% DNFB in a 4:1 acetone/olive oil solution is applied to the leftinner and outer ear surface. This application results in the inductionof swelling to the left ear and under these conditions, all animalsresponded to this treatment with ear swelling. A vehicle controlsolution of 4:1 acetone/olive oil is applied to the right inner andouter ear. Twenty four hours later, mice are anaesthetized, andmeasurements of the left and right ear are taken using a digitalmicrometer. The difference between the two ears is recorded as theamount of swelling induced by the challenge of DNFB. Drug treatmentgroups are compared to vehicle control to generate the percent reductionin ear swelling. Dexamethasone is routinely used as a positive controlas it has broad anti-inflammatory activity.

Example 240 Peptidoglycan-Polysaccharide Rat Arthritic Model

(a) Systemic Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflurane in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals are injected intraperitoneally (i.p.)with a single injection of purified PG-PS 10S Group A, D58 strain(concentration 25 μg/g of bodyweight) suspended in sterile 0.85% saline.Each animal receives a total volume of 500 microliters administered inthe lower left quadrant of the abdomen using a 1 milliliter syringe witha 23 gauge needle. Placement of the needle is critical to avoidinjecting the PG-PS 10S into either the stomach or caecum. Animals areunder continuous observation until fully recovered from anesthesia andmoving about the cage. An acute response of a sharp increase in anklemeasurement, typically 20% above baseline measurement can peak in 3-5days post injection. Treatment with test compounds can be PO, SC, IV orIP. Rats are dosed no more than two times in a 24 hour time span.Treatment can begin on day 0 or any day after that through day 30. Theanimals are weighed on days 0, 1, 2, 3, 4, 5, 6, 7 and beginning againon day 12-30 or until the study is terminated. Paw/ankle diameter ismeasured with a digital caliper on the left and right side on day 0prior to injection and again on day 1, 2, 3, 4, 5, 6 and 7. On day 12,measurements begin again and continue on through day 30. At this time,animals can be anesthetized with isoflurane, as described above, andterminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are then euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

(b) Monoarticular Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflurane in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals are injected intra-articular (i.a.)with a single injection of purified PG-PS 100P Group A, D58 strain(concentration 500 μg/mL) suspended in sterile 0.85% saline. Each ratreceives a total volume of 10 microliters administered into thetibiotalar joint space using a 1 milliliter syringe with a 27 gaugeneedle. Animals are under continuous observation until fully recoveredfrom anesthesia and moving about the cage. Animals that respond 2-3 dayslater with a sharp increase in ankle measurement, typically 20% abovebaseline measurement on the initial i.a. injection, are included in thestudy. On day 14, all responders are anesthetized again using theprocedure previously described. Animals receive an intravenous (I.V.)injection of PG-PS (concentration 250 μL/mL). Each rat receives a totalvolume of 400 microliters administered slowly into the lateral tail veinusing a 1 milliliter syringe with a 27 gauge needle. Baseline anklemeasurements are measured prior to IV injection and continue through thecourse of inflammation or out to day 10. Treatment with test compoundswill be PO, SC, IV or IP. Rats are dosed no more than two times in a 24hour time span. Treatment can begin on day 0 or any day after thatthrough day 24. The animals are weighed on days 0, 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. Paw/anklediameter is measured with a digital caliper on the left and right sideon day 0 prior to injection and again on day 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. At thistime, animals can be anesthetized with isoflurane, as described above,and terminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are them euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

Example 241 Mice Models for Asthma

Efficacy of a compound provided herein in treating, preventing and/ormanaging asthma can be assessed using an conventional animal modelsincluding various mice models described in, for example, Nials et al.,Dis Model Mech. 1(4-5): 213-220 (2008).

(a) Acute Allergen Challenge Models

Several models are known in the art and any of such models can be used.Although various allergens can be used to induce asthma-like conditions,the principle is consistent throughout the methods. Briefly, asthma-likeconditions are induced through multiple systemic administration of theallergen (e.g., ova, house dust mite extracts and cockroach extracts) inthe presence of an adjuvant such as aluminum hydroxide. Alternatively,an adjuvant-free system can be used, but it usually requires a highernumber of exposures to achieve suitable sensitization. Once induced,animals exhibit many key features of clinical asthma such as: elevatedlevels of IgE; airway inflammation; goblet cell hyperplasia; epithelialhypertrophy; AHR ro specific stimuli; and early and late phasebronchoconstriction. Potential efficacy of a compound thus can beassessed by determining whether one or more of these clinical featuresare reversed or mitigated.

(b) Chronic Allergen Challenge Models

Chronic allergen challenge models aim to reproduce more of the featuresof the clinical asthma, such as airway remodeling and persistent AHR,than acute challenge models. While allergens similar to those used inacute allergen challenge models can be used, in chronic allergenchallenge models, animals are subjected to repeated exposure of theairways to low levels of allergen for a period of up to 12 weeks. Onceinduced, animals exhibit key features of human asthma such as:allergen-dependent sensitization; a Th2-dependent allergic inflammationcharacterized by eosinophillic influx into the airway mucosa; AHR; andairway remodeling as evidenced by goblet cell hyperplasia, epithelialhypertrophy, subepithelial or peribronchiolar fibrosis. Potentialefficacy of a compound thus can be assessed by determining whether oneor more of these clinical features are reversed or mitigated.

Example 242 Models for Psoriasis

Efficacy of a compound provided herein in treating, preventing and/ormanaging psoriasis can be assessed using an conventional animal modelsincluding various animal models described in, for example, Boehncke etal., Clinics in Dermatology, 25: 596-605 (2007).

As an example, the mouse model based on adoptive transfer ofCD4⁺CD45RB^(hi) T cells described in Hong et al., J. Immunol., 162:7480-7491 (1999) can be made. Briefly, female BALB/cBY (donor) andC.B.-17/Prkdc scid/scid (recipient) mice are housed in a specificpathogen-free environment and are used between 6 and 8 weeks of age.CD4⁺ T cells are enriched from BALB/cBy splenocytes using a mouse CD4enrichment kit. The cells are then labeled with PE-conjugated anti-CD4,FITC-conjugated anti-CD45RB, and APC-conjugated anti-CD25 antibodies.Cells are sorted using a cell sorter. CD4⁺CD45RB^(hi)CD25 cells arecollected. Cells are resuspended in saline and 4×10⁸ cells/mouse areinjected i.p. into C.B.-17/Prkdc scid/scid mice. Mice may be dosed withLPS, cytokines, or antibodies as necessary. Mice are monitored forexternal signs of skin lesions twice each week. After the termination,ear, back skin, lymph nodes and spleen may be collected for further exvivo studies.

Example 243 Models for Scleroderma

A compound's efficacy in treating scleroderma can be tested using animalmodels. An exemplary animal model is a mouse model for sclerodermainduced by repeated local injections of bleomycin (“BLM”) described, forexample, in Yamamoto et al., J Invest Dermatol 112: 456-462 (1999), theentirety of which is incorporated herein by reference. This mouse modelprovides dermal sclerosis that closely resembles systemic sclerosis bothhistologically and biochemically. The sclerotic changes observed in themodel include, but are not limited to: thickened and homogenous collagenbundles and cellular filtrates; gradual increase in number of mastcells; degranulation of mast cells; elevated histamine release; increasein hydroxyproline in skin; presence of anti-nuclear antibody in serum;and strong expression of transforming growth factor β-2 mRNA. Therefore,efficacy of a compound in treating scleroderma can be assessed bymonitoring the lessening of one or more of these changes.

Briefly, the following exemplary procedures can be used to generate themouse model for scleroderma: Specific pathogen-free, female BALB/C miceand C3H mice of 6 weeks old, weighing about 20 g, are purchased andmaintained with food and water ad libitum. BLM is dissolved in PBS atdiffering concentrations and sterilized with filtration. Aliquots ofeach concentration of BLM or PBS are injected subcutaneously into theshaved back of the mice daily for 1-4 weeks with a needle.Alternatively, mice are injected every other day.

Histolopathological and biochemical changes induced can be assessedusing any methods commonly practiced in the field. For example,histopathological changes can be assessed using a standardavidine-biotin peroxidase technique with anti-L3T4 monoclonal antibody,anti-Lyt2 monoclonal antibody, anti-mouse pan-tissue-fixed macrophageantibody, anti-stem cell factor monoclonal antibody, anti-transforminggrowth factor-β polyclonal antibody, and anti-decorin antibody. Cytokineexpression of cellular infiltrates can be assessed by using severalanti-cytokine antibodies. Hydroxyproline level can be assessed byhydrolyzing skin pieces with hydrochloric acid, neutralizing with sodiumhydroxide, and colorimetrically assessing the hydrolates at 560 nm withp-dimethylaminobenzaldehyde. Pepsin-resistant collagen can be assessedby treating collagen sample extracted from biopsied tissues andanalyzing by polyacrylamide stacking gel electrophoresis. Mast cells canbe identified by toluidine blue, and cells containing matachromaticgranules can be counted under high magnification of a light microscope.Serum levels of various cytokines can be assessed by enzyme-linkedimmunosorbent assay, and mRNA levels of the cytokines can be assessed byreverse-transcriptase polymerase chain reaction. Autoantibodies in serumcan be detected using 3T3 fibroblasts as the substrate for thescreening.

Example 244 Models for Myositis

A compound's efficacy in treating myositis (e.g., dermatomyositis) canbe tested using animal models known in the art. One such example is thefamilial canine dermatomyositis model described in Hargis et al., AJP120(2): 323-325 (1985). Another example is the rabbit myosin inducedmouse model described in Phyanagi et al., Arthritis & Rheumatism,60(10): 3118-3127 (2009).

Briefly, 5-week old male SJL/J mice are used. Purified myosin fromrabbit skeletal muscle (6.6 mg/ml) is emulsified with an equal amount ofFreund's complete adjuvant and 3.3 mg/ml Mycobacterium butyricum. Themice are immunized repeatedly with emulsified rabbit myosin. Oncemyositis is induced, inflammatory cell filtration and necrotic musclefiber should be evident in the model. In the muscles of animals, CD4⁺ Tcells are mainly located in the perimysum and CD8⁺ T cells are mainlylocated in the endomysium and surround non-necrotic muscle fibers. TNFα,IFNγ and perforin are up-regulated and intercellular adhesion molecule 1is increased in the muscles.

To assess the efficacy of a compound, following administration of thecompound through adequate route at specified dose, the mice are killedand muscle tissues are harvested. The muscle tissue is immediatelyfrozen in chilled isopentane precooled in liquid nitrogen, and thencryostat sections are prepared. The sections are stained withhematoxylin and eosin for counting of number of infiltrated cells. Threesections from each mouse are prepared and photomicrographs are obtained.For immunohistochemical tests, cryostat sections of muscle are dried andfixed in cold acetone at −20° C. The slides are rehydrated in PBS, andthen endogeneous peroxide activity is blocked by incubation in 1%hydrogen peroxide. The sections are incubated overnight with ratanti-mouse CD4 monoclonal antibody, rat anti-mouse CD8 monoclonalantibody, rat anti-mouse F4/80 monoclonal antibody or normal rat IgG inantibody diluent. The samples are washed with PBS and incubated withbiotin-conjugated rabbit anti-rat IgG pretreated with 5% normal mouseserum. After washing with PBS, the samples are incubated withstreptavidin-horseradish peroxidase. After washing PBS, diaminobenzidineis used for visualization.

Example 245 Models for Sjögren Syndrome

A compound's efficacy in treating Sjögren's syndrome can be tested usinganimal models known in the art, for example, those described in Chioriniet al., Journal of Autoimmunity 33: 190-196 (2009). Examples include:mouse model spontaneously developed in first filial generation of NZBmice crossed to NZW mice (see, e.g., Jonsson et al., Clin ImmunolImmunopathol 42: 93-101 (1987); mouse model induced by i.p. injection ofincomplete Freund's adjuvant (id.; Deshmukh et al., J Oral Pathol Med38: 42-27 (2009)); NOD mouse models wherein Sjögren's phenotype isdeveloped by specific genotypes (see, e.g., Cha et al., Arthritis Rheum46: 1390-1398 (2002); Kong et al., Clin Exp Rheumatol 16: 675-681(1998); Podolin et al., J Exp Med 178: 793-803 (1993); and Rasooly etal., Clin Immunol Immunopathol 81: 287-292 (1996)); mouse modeldeveloped in spontaneous lpr mutation; mouse model developed in Id3knock-out mice (see, e.g., Li et al., Immunity 21: 551-560 (2004));mouse model developed in PI3K knock-out mice (see, e.g., Oak et al.,Proc Natl Acad Sci USA 103: 16882-16887 (2006)); mouse model developedin BAFF over-expressing transgenic mice (see, e.g., Groom et al., J ClinInvest 109: 59-68 (2002)); mouse model induced by injection of Roantigen into BALB/c mice (see, e.g., Oh-Hora et al., Nat. Immunol 9:432-443 (2008)); mouse model induced by injection of carbonic anhydraseII (see, e.g., Nishimori et al., J Immunol 154: 4865-4873 (1995); mousemodel developed in IL-14 over-expressing transgenic mice (see, e.g.,Shen et al., J Immunol 177: 5676-5686 (2006)); and mouse model developedin IL-12 expressing transgenic mice (see, e.g., McGrath-Morrow et al.,Am J Physiol Lung Cell Mol Physiol 291: L837-846 (2006)).

Example 246 Models for Immune Complex Mediated Disease

The Arthus reaction is a type 3 immune response to immune complexes, andthus, can be a mechanistic model supporting therapeutic hypothesis forimmune complex mediated diseases such as rheumatoid arthritis, lupus andother autoimmune diseases. For example, PI3Kγ and δ deficient mice canbe used as experimental models of the Arthus reaction and provideassessment of therapeutic potential of a compound as to the treatment ofimmune complex mediated diseases. The Arthus reaction can be inducedusing the following exemplary procedures as described in Konrad et al.,Journal of Biological Chemistry (2008 283(48): 33296-33303.

PI3Kγ- and PI3Kδ-deficient mice are maintained under dry barrierconditions. Mice are anesthetized with ketamine and xylazine, and thetrachea is cannulated. Appropriate amount of protein G-purified anti-OVAIgG Ab is applied, and appropriate amount of OVA antigen is givenintravenously. For PI3K blocking experiments, wortmanin is givenintratracheally together with the application of anti-OVA IgG. Mice arekilled at 2-4 hours after initiation of inflammation, and desired followup assessments can be performed using methods known in the art.

Example 247 PI3-Kinase Promega™ Assay

Promega ADP-Glo Max assay kit (Cat. No. V7002) was utilized to determineIC₅₀ values for α, β, δ and γ isoforms of human Class I PI3 kinases(Millipore). Samples of kinase (20 nM α or δ, 40 nM β or γ isoform) wereincubated with compound for 15 minutes at room temperature in reactionbuffer (15 mM HEPES pH 7.4, 20 mM NaCl, 1 mM EGTA, 0.02% Tween 20, 10 mMMgCl₂, 0.2 mg/mL bovine-γ-globulins) followed by addition ofATP/diC8-PtdInsP mixture to give final concentrations of 3 mM ATP and500 uM diC₈-PtdInsP. Reactions were incubated at room temperature for 2hours followed by addition of 25 uL of stop solution. After a 40-minuteincubation at room temperature, 50 uL of Promega detection mix was addedfollowed by incubation for 1 hour at room temperature. Plates were thenread on Envision plate reader in luminescence mode. Data was convertedto % inhibition using the following equation below:

${\%\mspace{14mu}{inhibition}} = {100 - \left( {\left\lbrack \frac{S - {Pos}}{{Neg} - {Pos}} \right\rbrack*100} \right)}$where S is the sample luminescence, Pos is a positive control withoutadded PI3K, Neg is the negative control without added compound. Data wasthen plotted as % inhibition vs compound concentration. Data fit to 4parameter logistic equation to determine IC₅₀ values:

${\%\mspace{14mu}{inhibition}} = \frac{\max - \min}{1 - \left( \frac{{IC}_{50}^{h}}{\lbrack I\rbrack^{h}} \right)}$

Certain compounds provided herein were tested in PI3-Kinase PromegaAssay using procedures as described above to determine IC₅₀ values forα, β, δ and/or γ isoforms. The IC₅₀ values are summarized in Table 2.

Example 248 Isoform-Selective Cellular Assays

(a) PI3K-δ Selective Assay

A compound's ability in selectively inhibiting PI3K-β can be assessedusing RAJI cells, i.e., B lymphocyte cells derived from lymphomapatients. Briefly, serum-starved RAJI cells are stimulated withanti-human IgM, thereby causing signaling through the B-cell receptors,as described in, for example, He et al., Leukemia Research (2009) 33:798-802. B-cell receptor signaling is important for the activation,differentiation, and survival of B cells and certain B-cell derivedcancers. Reduction of phospho-AKT is indicative of compounds that mayinhibit B-cell proliferation and function in certain diseases. Bymonitoring the reduction of phospho-AKT in stimulated RAJI cells (usingfor example, phospho-AKT antibodies), a compound's potential efficacy inselectively inhibiting PI3Kδ can be assessed.

Certain compounds provided herein were tested in RAJI cell model usingprocedures as described above. The IC₅₀ values for phospho-AKT aresummarized in Table 2.

(b) PI3K-γ Selective Assay

A compound's ability in selectively inhibiting PI3K-γ can be assessedusing RAW264.7 macrophages. Briefly, serum-starved PAW264.7 cells arestimulated with a known GPCR agonist C5a. See, e.g., Camps et al.,Nature Medicine (2005) 11(9):936-943. Cells can be treated with testcompounds prior to, simultaneously with, or subsequent to thestimulation by C5a. RAW 264.7 cells respond to the complement componentfragment C5a through activation of the C5a receptor, and the C5areceptor activates macrophages and induces cell migration. Testcompounds' ability to inhibit C5a-mediated AKT phosphorylation isindicative of selective inhibition of PI3K-γ. Thus, by monitoring thereduction of phospho-AKT in stimulated RAW 264.7 cells (using forexample, phospho-AKT antibodies), a compound's potential efficacy inselectively inhibiting PI3Kγ can be assessed.

Certain compounds provided herein were tested in RAW 264.7 cell modelusing procedures as described above. The IC₅₀ values for phospho-AKT aresummarized in Table 2.

(c) PI3K-α Selective Assay

A compound's ability in selectively inhibiting PI3K-α can be assessedusing SKOV-3 cells, i.e., human ovarian carcinoma cell line. Briefly,SKOV-3 cells, in which mutant PI3Kα is constitutively active, can betreated with test compounds. Test compounds' ability to inhibit AKTphosphorylation in SKOV-3 cells, therefore, is indicative of selectiveinhibition of PI3Kα. Thus, by monitoring the reduction of phospho-AKT inSKOV-3 cells (using for example, phospho-AKT antibodies), a compound'spotential efficacy in selectively inhibiting PI3Kα can be assessed.

(d) PI3K-β Selective Assay

A compound's ability in selectively inhibiting PI3K-β can be assessedusing 786-O cells, i.e., human kidney carcinoma cell line. Briefly,786-O cells, in which PI3Kβ is constitutively active, can be treatedwith test compounds. Test compounds' ability to inhibit AKTphosphorylation in 786-O cells, therefore, is indicative of selectiveinhibition of PI3Kβ. Thus, by monitoring the reduction of phospho-AKT in786-O cells (using for example, phospho-AKT antibodies), a compound'spotential efficacy in selectively inhibiting PI3Kβ can be assessed.

What is claimed is:
 1. A compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein Cy is 6-membered aryl substituted by 1 occurrence of R³ and 0,1, 2, or 3 occurrence(s) of R⁵; W_(b) ⁵ is CR⁸ or CHR⁸; R⁸ is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino,acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro; B ishydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl, each of which is substituted with 0, 1, 2, 3, or 4occurrence(s) of R²; each R² is independently alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, orcarbonate; X is —(CH(R⁹))_(z)—; Y is —NH—C(═O)—, —C(═O)—N(R⁹)—, or—C(═O)—N(R⁹)—(CHR⁹)—; z is an integer of 1, 2, 3, or 4; R³ is alkyl,cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido,amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone,sulfonamido, halo, cyano, aryl, heteroaryl, hydroxyl, or nitro; each R⁵is independently alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro; each R⁹ is independently hydrogen, alkyl, cycloalkyl,heterocyclyl, or heteroalkyl; or two adjacent occurrences of R⁹ togetherwith the atoms to which they are attached form a 4- to 7-membered ring;W_(d) is

X₁, X₂ and X₃ are each independently C, CR¹³, or N; X₄, X₅ and X₆ areeach independently N, NH, CR¹³, S, or O; and wherein R¹⁰, R¹¹, R¹², andR¹³ are each independently hydrogen, alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate,urea, carbonate, or NR′R″ wherein R′ and R″ are taken together withnitrogen to form a cyclic moiety.
 2. The compound of claim 1, havingFormula (IIIb):

wherein R⁸ is hydrogen, alkyl, cyano, or halo; R⁹ is hydrogen or alkyl,and Y is —NH—C(O)—.
 3. The compound of claim 1, having a structure ofFormula (II):


4. The compound of claim 1, having a structure of Formula (IIIa) orFormula (IIIb):


5. The compound of claim 1, wherein R³ is halo, cyano, hydroxy, alkyl,alkoxy, amino, acyl, heteroaryl, aryl, heterocyclyl, or cycloalkyl. 6.The compound of claim 5, wherein R³ is heteroaryl, aryl, alkyl,haloalkyl, OH, Cl, or F.
 7. The compound of claim 6, wherein R³ isheteroaryl, phenyl, CH₃, CF₃, OH, or Cl.
 8. The compound of claim 5,wherein R³ is CH₃, OCH₃, CF₃, or halo.
 9. The compound of claim 5,wherein R³ is OCF₃, CN, cyclopropyl, CH₂OH, amino, formyl, orheterocyclyl.
 10. The compound of claim 1, wherein R⁸ is H, CH₃, OCH₃,CF₃, CN, or halo.
 11. The compound of claim 1, wherein B is aryl,heteroaryl, alkyl, cycloalkyl, or heterocyclyl, each of which issubstituted with 0, 1, 2, or 3 occurrence(s) of R².
 12. The compound ofclaim 1, wherein B is phenyl substituted with 0, 1, 2, or 3occurrence(s) of R².
 13. The compound of claim 1, wherein B isunsubstituted phenyl.
 14. The compound of claim 1, wherein B is phenylsubstituted with 1 or 2 occurrence(s) of R².
 15. The compound of claim14, wherein R² is halo or alkyl.
 16. The compound of claim 1, wherein Bis methyl, isopropyl, or cyclopropyl.
 17. The compound of claim 1,wherein B is cyclohexyl or alkyl.
 18. The compound of claim 1, whereinW_(d) is:

wherein one of X₁ and X₂ is N and one of X₁ and X₂ is C or CR¹³; and X₃is CR¹³ or N.
 19. The compound of claim 1, wherein W_(d) is:


20. The compound of claim 1, wherein W_(d) is:


21. The compound of claim 1, wherein W_(d) is:


22. The compound of claim 1, wherein W_(d) is:


23. The compound of claim 1, wherein W_(d) is:


24. The compound of claim 1, wherein W_(d) is


25. The compound of claim 18, wherein R¹⁰ is NH₂.
 26. The compound ofclaim 1, wherein X is —CH₂— or —CH(CH₃)—.
 27. The compound of claim 26,wherein X is —CH(CH₃)—.
 28. The compound of claim 27, wherein the CHcarbon of the —CH(CH₃)— moiety has an (S) stereochemical configuration.29. The compound of claim 27, wherein the CH carbon of the —CH(CH₃)—moiety has an (R) stereochemical configuration.
 30. The compound ofclaim 1, wherein Y is —NH—C(O)—.
 31. The compound of claim 1, wherein—X—Y— is —CH₂—N(CH₃)—C(O)—.
 32. The compound of claim 1, wherein —X—Y—is (S)—CH(CH₃)—NH—C(O)—.
 33. The compound of claim 1, wherein —X—Y— is(R)—CH(CH₃)—NH—C(O)—.
 34. A pharmaceutical composition comprising acompound of claim 1, and a pharmaceutically acceptable excipient,diluent, or carrier.
 35. The compound of claim 1, wherein the compoundis

or a pharmaceutically acceptable form thereof.
 36. The compound of claim35, wherein the compound is

or a pharmaceutically acceptable form thereof.
 37. The compound of claim36, wherein the compound is

Compound 116, or a pharmaceutically acceptable form thereof.
 38. Thecompound of claim 36, wherein the compound is

or a pharmaceutically acceptable form thereof.
 39. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable form thereof.
 40. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable form thereof.
 41. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable form thereof.
 42. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable form thereof.
 43. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable form thereof.
 44. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable form thereof.
 45. A compound of Formula(II):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable form thereof,wherein R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl or nitro; B is hydrogen, alkyl, amino, heteroalkyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which issubstituted with 0, 1, 2, 3, or 4 occurrence(s) of R²; each R² isindependently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy,amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, or carbonate; X is —(CH(R⁹))_(z)—; Yis —N(R⁹)—C(═O)—, —C(═O)—N(R⁹)—, or —C(═O)—N(R⁹)—(CHR⁹)—; z is aninteger of 1, 2, 3, or 4; R³ is alkyl, cycloalkyl, heterocyclyl,fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl,sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl,heteroaryl, hydroxyl, or nitro; each R⁹ is independently hydrogen,alkyl, cycloalkyl, heterocyclyl, or heteroalkyl; or two adjacentoccurrences of R⁹ together with the atoms to which they are attachedform a 4- to 7-membered ring; W_(d) is

X₁, X₂ and X₃ are each independently C, CR¹³, or N; X₄, X₅ and X₆ areeach independently N, NH, CR¹³, S, or O; and wherein R¹⁰, R¹¹, R¹², andR¹³ are each independently hydrogen, alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate,urea, carbonate, or NR′R″ wherein R′ and R″ are taken together withnitrogen to form a cyclic moiety.
 46. A pharmaceutical compositioncomprising a compound of claim 37, and a pharmaceutically acceptableexcipient, diluent, or carrier.
 47. A pharmaceutical compositioncomprising a compound of claim 38, and a pharmaceutically acceptableexcipient, diluent, or carrier.
 48. The compound of claim 45, whereinthe compound is

or a pharmaceutically acceptable form thereof.